Tracer particles, and methods for making same

ABSTRACT

The invention relates to tracer particles for product identification and/or authentication. When incorporated into a manufactured item, that item can be subsequently authenticated by detecting the tracer particle. The tracer particles of the invention are etched with markings, and in some embodiments, are manufactured with materials that are generally recognized as safe (GRAS). The particles can be analyzed qualitatively or quantitatively. In other aspects, the invention provides methods for the manufacture of the tracer particles, and in other aspects, provides methods for using the particles. Examples of products that can be tagged using the tracer particles of the invention include pharmaceuticals, animal feeds or feed supplements, baby formula powder and liquid bulk materials. Other applications include forensics, such as in explosive materials.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/080,648, filed Nov. 14, 2013, and further claims benefit of U.S.Provisional Applications with Serial Nos. 61/796,570, filed Nov. 15,2012, and 61/851,244, filed Mar. 4, 2013, each of which are hereinincorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention relates generally to tracer particles, and methods formaking the tracer particles. The tracer particles described herein finda variety of uses, for example, for tagging manufactured items that canbe subsequently authenticated by either detecting, or failing to detect,the tracer particle in the item at any point post-manufacture. Examplesof products that can be tagged using the tracer particles of theinvention include pharmaceuticals, animal feeds or feed supplements, andbaby formula. Other applications include forensics, such as for tracingthe source of materials used to manufacture explosives.

BACKGROUND OF THE INVENTION

Counterfeit products pose a major threat in many industries, both in theform of public safety as well as pecuniary losses. One industry facingthe wide-spread problems of counterfeiting is the pharmaceuticalindustry. The challenges of controlling counterfeit drugs have increasedas pharmaceutical markets become more international. For example, drugmanufacturing can involve importing materials from other countries, inaddition to distributing finished products across international borders.As a result, additional handlers, repackagers and distributors in avariety of locations are required in the product supply chains, therebyrendering proprietary drugs even more vulnerable to tampering and fraud.These complex supply chains create entry points through whichcontaminated, adulterated and counterfeit products can infiltrate thedrug supply.

Counterfeiting activities in oral pharmaceuticals can take variousforms, such as (i) entirely fraudulent products containing no activeingredient, (ii) diluted, generic or insufficient dosages of the activeingredient, contrary to the labeled dosages on the packaging or (iii)substitution of the intended active ingredient with a different orinferior drug to elicit a similar physiological response. In addition,some fraudulent pharmaceuticals contain harmful or toxic ingredients.Counterfeit pharmaceutical products that fail to deliver critical activeingredients, or inflict toxic effects, pose a significant threat topublic safety.

There are documented cases of counterfeiters targeting a wide range ofprescription and non-prescription products, such as vaccines, coughsyrup, anti-malarial drugs, heparin, painkillers, blood thinners,dietary supplements, teething medicines, hypertensive medicines,steroids. Products that are expensive and/or high demand inunderdeveloped countries are attractive targets for counterfeitingactivity. Counterfeit drugs can lead to illness, increased health risksand in extreme cases involving diethylene glycol (DEG) and melamine,have been fatal.

Governmental regulatory agencies, both in the U.S. and abroad, havestruggled to detect, prevent, and address drug contamination andcounterfeiting issues. Limited governmental resources and a lack ofinternational consensus have hindered the implementation of global,uniform drug control practices. In order to be effective, agencies needto agree on what constitutes a counterfeit drug, the high-riskproprietary drugs, product traceability and authentication systems andsampling/testing protocols at international borders. Undeveloped andunderdeveloped nations are particularly vulnerable to the activities ofdrug counterfeiters.

The pharmaceutical industry has focused on unique packaging that allowthe end users to discern authentic from counterfeit products. Theseefforts have included barcodes, holographic labels, laser encryptedlabels, color shifting security ink, and DNA reagent markers. Ideally,these packaging security features should be easily identifiable, yetdifficult to duplicate. Unfortunately, over time, increasinglysophisticated forgery efforts have adapted many of these packagesecurity measures.

In addition to marking drug packaging the actual drugs can be markedwith a security feature to authenticate the product. This direct markingapproach has various benefits. If a legitimate drug manufacturer is ableto mark his pharmaceutical product with an identifying physical tag atthe time of manufacture, this will enable a health professional todetermine if the drug is genuine at any point post-production. Such drug“tracers” are called tags, microtags, taggants, markers and/ormicroparticles. Detection, or lack thereof, of these tracers in apharamacutical product will ideally serve as a marker to indicate drugauthenticity or drug fraudulence, respectively.

The need for security control measures to thwart counterfeiting andproduct tampering extend to a variety of industries, including variousfoods and other types of consumables. Well known examples ofcounterfeiting and tampering exist in powdered and liquid baby formula,animal feed, pet foods, cigarettes, plastics and replacement airbags.There is also a need for tracer particles in forensic applications, suchas coding for the source of explosive materials.

Various tagging technologies for the authentication of marked goods havebeen proposed, including systems for drug marking and drug tracing.Tracers have also been described for coding the source of dynamite andblack powder. However, these proposed systems have various drawbacks.Limitations of these existing tracer systems include the large sizes ofthe tracer particles, making them unsuitable in applications such ascoding human pharmaceuticals. Other significant limitations in thetracer particles art include particles that are not suitable for humanor animal ingestion, tracers that are expensive to produce, and theanalytical procedures to detect and/or quantify such tracers either havenot been developed, are expensive, are time consuming, are not readilyportable, or require materials or reagents that are not readilyavailable.

What is needed in the art are improved tracer particles and associatedtechniques for monitoring counterfeit/fraudulent products, or productsthat have been subject to tampering. Ideally, these improved systemswill permit cost-effective sampling and testing for product integrity.Also what is needed in the art are tracers that are suitable foringestion.

What is needed in the art are improved tracer particles that can beadded directly to an oral pharmaceutical formulation at the time ofmanufacture, in parallel with the active ingredient. This type of drugtracer should be undetectable or sufficiently complex to thwartcounterfeiters from detecting or reproducing the tracer particles.Ideally, methods for detection of the tracer in the manufactured productshould be non-complex and use equipment that is readily available andideally also portable. Such drug tracers will permit determination ofpharmaceutical authenticity anywhere along the post-production stream ofcommerce. Optionally, this type of authenticity control can be donecovertly by the drug manufacturer.

The present invention, in its many embodiments, provides compositionsand methods for product security that overcome challenges in theindustry, and provide many benefits previously unrealized in other typesof security products. In addition, still further benefits flow from theinvention described herein, as will be apparent upon reading the presentdisclosure.

SUMMARY OF THE INVENTION

The invention described herein provides compositions, and methods forproducing those compositions, that solve industry problems associatedwith monitoring product security and detecting counterfeit or tamperedgoods. The invention has diverse applications, including the field ofcounterfeit pharmaceutical detection.

The invention provides tracer particles that find a variety of uses. Theparticles are magnetic, and are characterized by at least onedistinguishing marking on the surface of the particle, where the markingdoes not exceed about 40 microns in any dimension. Particles withsmaller markings are also provided for example, with markings that donot exceed about 20 microns in size. Particles with markings betweenabout 500 nanometers and about 20 microns are also provided. Themagnetic particles can be any desired size, for example, not exceedingabout 400 microns in any dimension, or smaller particles such as notexceeding about 100 microns or about 50 microns in size. The magneticmaterial in the particles can be any magnetic material, for example,iron, nickel, gamma-ferrioxide, ferrites, or any combinations ofmaterials. The markings used on the tracer particles can be alphanumericcharacters, but are not limited to alphanumeric characters. The tracerparticles can optionally contain additional features that facilitatedetection and analysis, such as a fluorescent material, a thermochromicmaterial, a chromogenic material or any type of chromophore.

The tracer particles can be incorporated into any of a variety ofproducts to generate marked articles that can later be authenticated,including marked pharmaceutical products.

When a marked pharmaceutical product is generated, that marked productcontains at least one excipient from the drug manufacture process, andthe tracer particles that are dispersed in the pharmaceutical product,or can be localized in the pharmaceutical product, such as in a tabletcoating. In some embodiments of marked pharmaceutical products, thetracer particles in the product are preferably smaller than about 100microns in any dimension, or smaller, for example, smaller than about 80microns or smaller than about 50 microns. When producing a particle thatis smaller than about 100, or 80 or 50 microns in size forpharmaceutical use, the distinguishing marking on that particle can bemarkings that do not exceed about 10 microns in any dimension, but inpreferred embodiments, smaller markings, for example smaller than about5 microns or 2 microns can be used. When used in the pharmaceuticals,the particles are ingestible, and are made from materials generallyregarded as safe for human consumption. The tagged pharmaceuticals canbe in solid formulations or liquid formulations.

Tracer particles of the invention can also be used to produce markedanimal feeds, such as formula feeds. The magnetic tracer particles areincorporated into the bulk matter feed mix. That feed mix can later betested and authenticated by ascertaining the presence or absence of thetracer particles. The tracer particles used to generate the taggedanimal feed can be limited to particles not more than about 350 micronsin size. The markings on the particles are generally not larger thanabout 40 microns, although smaller particle populations can also beused.

The invention provides a generalized method for producing markedproducts, where the method consists essentially of dispersing themagnetic tracer particles throughout a flowable bulk material. Theparticles are not particularly limited in size, but may be restricted toparticles smaller than about 400 microns, or smaller than about 100microns or 50 microns. In some instances, the size of the magneticparticles that are used is a bracketed range, for example, between about35 and 50 microns, or between about 50 and 80 microns, or between 80 and150 microns, or between 250 and 400 microns. The particles used to makethe marked products generally contain at least one distinguishing markthat is not larger than about 40 microns in any dimension, althoughsmaller size markings such as smaller than 20 microns, may bepreferable. The flowable bulk material can be dry bulk particulatematerial or liquid bulk material. Examples of marked products includespharmaceuticals (human and animal), baby formula powder, premixed liquidbaby formula, explosives, animal feed, and an animal feed premix.

The magnetic particles are used in a wide variety of securityapplications, most notably, to authenticate a product that has beentagged with the tracer particles. Generally, the method forauthenticating a product first starts with the manufacture of a markedproduct using the tracer particles as described above. A product can betested for authenticity any point after production by detecting thetracer particle in the bulk material of the product, or in an articleformed from the bulk material. If the tracer particle is detected in thetested product, authenticity of that product is confirmed. The detectingstep will involve more than one step, where generally, the first step isto isolate the tracer particles using magnetic separation, and a secondstep of visualization of the distinguishing mark on the surface of thetracer particle, generally using magnification such as from a low powermicroscope capable of observing surfaces of opaque objects usingincident light. Visualizing the particles can be facilitated by using asecondary detection mechanism that has been installed in or on theparticles, such as by the addition of any suitable chromogenic orfluorogenic materials, or suitable chromophores or fluorophores into oron the particles. Such materials can then be used to visualize theparticles by colorimetric detection or fluorometric detection, eithervisually or electronically detected.

The tracer particles of the invention are produced usingphotolithography based methodologies. In its simplest application, themagnetic tracer particles are produced using a traditionalphotolithography technique. This method generally follows the steps of(i) attaching a magnetic metal or metal containing substrate layer to anunderlying support layer; (ii) wet etching the substrate layer toproduce many copies of a distinguishing mark on the surface of thesubstrate layer; (iii) removing the marked substrate layer from thesupport layer; and (iv) fragmenting the marked substrate layer intoparticles, where the majority of particles are expected to contain atleast one copy of the distinguishing mark on the surface of theparticle. Particles of a desired size with markings of specifieddimensions can be produced.

In a variant method, microcontact printing is used to produce the tracerparticles. This method generally follows the steps of (i) creating amaster template from iron, steel or silicone, and etching many copies ofa distinguishing mark on the surface of the master template, (ii) makingan elastomeric stamp from the master template, (iii) imprinting themarks that are on the stamp onto a magnetic substrate layer bycontacting the stamp to the magnetic substrate layer with a suitableink, (iv) wet etching the magnetic substrate layer according to the inkimprint, and (v) removing the magnetic substrate layer as a sheet andfragmenting the sheet into a powder or granular state, thereby makingthe tracer particles. The substrate layer from which the tracerparticles are formed can be a metal layer, such as an iron foil, or canbe a polymer film containing a magnetic powder additive.

In a third method, plasma etching is used to produce the magnetic tracerparticles. This method generally follows the steps of (i) providing amagnetic metal (such as an iron foil) or a magnetic metal-containingsubstrate layer (such as a polymer that contains an iron powder) that isattached to an underlying support layer; (ii) plasma etching thesubstrate layer to produce many copies of a distinguishing mark on thesurface of the substrate layer; (iii) plasma etching the markedsubstrate layer to a depth that is the full thickness of the substratein a pattern that separates the distinguishing marks on the surface ofthe substrate from each other; and (iv) detaching the substrate layerfrom the underlying support, thereby releasing the magnetic tracerparticles. The sizes of the particles produced are not particularlylimited, except that this plasma etching can produce generally higherresolution compared to microcontact printing, permitting smallerparticle sizes (for example, smaller than about 50 microns or about 100microns) and smaller distinguishing marks (for example, smaller thanabout 20 microns, or 10 microns, or 2 microns).

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B provide schematics illustrating the theory oftraditional photolithography. FIG. 1A provides a schematic illustratingthe theory of positive working photoresist. FIG. 1B provides a schematicillustrating the theory of negative working photoresist.

FIG. 2 provides a schematic depicting the theory of microcontactprinting.

FIG. 3 provides a schematic depicting a method for the production oftracer particles of the invention using a plasma etching technique.

FIG. 4 provides a photomicrograph of an etched iron sheet that wasproduced using traditional direct photolithography.

FIG. 5 provides a photomicrograph of an etched iron sheet that wasproduced using microcontact printing photolithography.

FIG. 6 provides a photomicrograph of iron-containing ETHOCEL™ tracerparticles that were produced using microcontact printing.

FIG. 7 provides a schematic depicting one method for the isolation andvisualization of magnetic tracer particles of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides tracer particles, as well as methods forthe production of the tracer particles. These tracer particles, and themethods for making the same, have a number of advantages over the stateof the art, and have a wide variety of applications, which will beapparent from the present disclosure.

Most generally, the tracer particles of the invention are small (e.g.,not larger than about 400 micrometers (i.e., microns) in any onedimension, and can be used, for example, in formula feeds. In otherembodiments, the particles are not larger than about 100 microns in anyone dimension, and can be used, for example, in human pharmaceuticals.Particles having still larger or smaller dimensions, of any specifieddesired size, are also contemplated. In some embodiments, the particlescomprise only food grade materials, and are less than about 100 micronsin size. In other aspects, the particles are magnetically attractable tofacilitate their isolation for analysis. The particles can be furthercoded with fluorescent compounds to facilitate their analysis.

At least one surface of the particle contains some type of intentionalmarking, for example but not limited to alphanumeric characters, wherethe size and/or content of the marking will permit that marking to serveas an authenticating security feature. For example, a marking that isnot larger than about 40 microns in any dimension, such as a letter thatis not larger than 40 microns in width or height, can serve as anauthenticating feature. Such a marked particle can serve as anauthentication tag because illicit duplication of that particlecontaining that character (e.g., production by a counterfeiter) ishighly unlikely due to the sophistication required to produce the markedparticle. Markings of still smaller dimensions are also available, forexample, not larger than about 20 microns in any dimension, or 5microns, or 2 microns, or 500 nanometers.

The tracer particles of the invention are used to mark various products,where the tracer particles are incorporated into the product at the timeof manufacture of the article. The tracer particle will then serve as anauthentication tag to determine whether or not any given article in thestream of commerce is authentic (i.e., contains the tracer particle) orcounterfeit (i.e., does not contain the tracer particle), or has beensubjected to tampered (i.e., may contain quantitatively fewer detectabletracer particles as compared to the number of detectable tracer partiesthat would be expected in an authentic item). Still other uses for thesetracer particles includes quantifying mixing efficiency in formula feedsand other bulk materials, monitoring cross contamination and theassessing the presence or absence of coded micro-ingredients.

In some embodiments, tagged products are formed from flowable dry bulkparticulate materials such as powders or granulated materials, or anymixtures of such materials, and the end product of the manufacturingprocess remains in a flowable bulk particulate form, for example,infant/baby formula powders, explosives, animal feeds and animal feedpremixes or feed supplements. As used herein, the terms “flowable,”“flowability” or “flowing” or similar expressions describe materialsthat have the capacity to move by flow in a manner typicallycharacterized by liquids. These terms can refer to solids that are in aloose particulate state, such as powders or a granulated state.

However, it is not intended that the tagged products must remain in aflowable bulk particulate state. In some aspects of the invention,products formed from the tagged dry bulk particulate material do notremain in a flowable particulate state. For example, the manufacture oftablet style oral pharmaceuticals starts with combining and mixingvarious dry bulk particulate materials, and then subjecting the mixtureto various processes and conditions that result in a hardened solidobject (e.g., a tablet style pill). The tablet has lost the dry bulkparticulate properties of the starting materials, however, stillcomprises the tracer particle dispersed within the hardened bulkmaterial. This resulting solid pill that has been tagged with a tracerparticle of the invention is within the scope of the invention. Thetracer particles of the invention find use in producing many types oftagged pharmaceutical products.

In other embodiments, the tracer particles are used to tag bulkmaterials that have lost their flowable properties, and are transformedto solid objects. For example, this includes pharmaceuticals that are ina solid tablet form, and also includes polymers such as plastics thatare used in high-risk markets such as electronics, medical products,aviation and automotive industries.

It is not intended that the products that are tagged with the tracerparticles be limited to dry bulk particulate materials, or solid objectsformed from the dry bulk material. In other aspects of the invention,the products that are tagged with the tracer particles can be in aliquid form, or behave as a liquid. The use of flowable liquids as bulkmaterial (e.g., liquid excipients) to produce products such as medicinesfor oral delivery are known in the art and within the scope of theinvention. The liquid excipients that find use with the invention arenot limited, and can comprise aqueous or non-aqueous liquids, organicliquids such as some types of organic solvents, combinations ofmaterials that behave as liquids, such as colloids, suspensions andslurries, and liquefiable materials such as lipids.

The invention also provides methods for producing the tracer particlesof the invention. These methods use modified photolithographytechniques, and can incorporate both wet etching and dry etching (plasmaetching) protocols.

I. Magnetic Tracer Particles

The tracer particles of the invention are magnetic, i.e., they compriseat least one magnetic material in sufficient quantity to render theparticle magnetic, i.e., magnetically isolatable. The production and useof magnetic tracer particles facilitates isolation of the particles frombulk material, such as from pharmaceuticals that have been ground topowder form, or from animal feed or feed supplements that are in bulkparticulate or granular form. Tracer particles of the invention can beproduced from any suitable magnetic material, and are not limited inthat aspect.

Magnetic materials are, most generally, materials that display magnetismwhen in the presence of a magnetic field or in the presence of othermagnets. Particles of the invention can be magnetic due to the presenceof permanent magnet materials, which have persistent magnetic moments(creates its own magnetic field) caused by ferromagnetism. Ferromagneticand ferrimagnetic materials, which are the materials commonly referredto as “magnetic,” are attracted to a magnet, and can retainmagnetization to become magnets. Ferromagnetic materials include nickel,iron, cobalt, gadolinium and their alloys. Ferrimagnetic materials,which include the alloys alnico, ferrites, magnetite and lodestone,differ from ferromagnetic materials in their microscopic structure.

Particles of the invention can also be magnetic due to the presence ofparamagnetic, or superparamagnetic, materials. Paramagnetic materialsalso display magnetic properties when placed in a magnetic field, andare attracted to a magnetic field, but these materials do not retain anyresidual magnetism once removed from the magnetic field.

In some embodiments of the invention, the tracer particles aremanufactured directly from metal sheet substrates, such as iron sheetsor steel sheets, often in the form of a foil. These particles thusproduced are magnetic due to the metal used to form the substrate.

In other embodiments, the magnetic tracer particles can be produced frompolymer substrates, for example, food grade polymers, that have beensupplemented with a magnetic material such as a magnetic powder.Sufficient magnetic material is added to the polymer matrix to producepolymer matrix particles that display magnetism when placed in amagnetic field. The magnetic supplements can be, for example, aferromagnetic material, such as powders of iron, nickel,gamma-ferrioxide, ferrites, reduced iron, electrolytic iron, iron oxideor some types of stainless steel. The choice of any particular magneticmaterial to form a magnetic polymer tracer particle is not limiting. Forexample, magnetic powders of various size particles, compositions, andfrom various manufactures can be used.

In some embodiments, magnetic powder particle sizes can vary, forexample, between about one (1) and six (6) microns in size, but largeror small magnetic material grains can also be used. Magnetic powdersupplement concentration ranges of 3-10% by weight can be sufficient toproduce the magnetic polymer particles. Various commercial magneticpowder products can be used, for example, iron particles with sizesbetween 1-6 microns (Goodfellow Group; Coraopolis, Pa.), reduced ironwith particles sizes below 325 mesh, i.e., below 44 microns in size(North American Hoganas; Niagara Falls, N.Y.) or iron oxide withparticles sizes below 5 microns (Sigma-Aldrich; St. Louis, Mo.).

The magnetic tracer particles of the invention can be convenientlyisolated from a source material using a simple magnetic device, or byusing commercially available devices designed for the collection ofmagnetic particles from a bulk material, for example, a laboratorymagnetic separator such as the MicroTracer, Inc. Rotary Detector™, or arare earth magnetic probe (e.g., MSP100 Probe, 4B Components; Morton,Ill.).

In some embodiments, the magnetic tracer particles of the invention aredispersed in a solid article, such as a pharmaceutical tablet. In thiscase, the particles can be isolated by grinding or pulverizing the solidtablet to form a finely grained powder, and the particles can beseparated from that powder by using any suitable apparatus for isolationof magnetic particles from dry material. In some embodiments, themagnetic tracer particles of the invention are dispersed in a liquid orliquid-like product, such as a liquid-containing capsule, a liquidmedication, or a colloid, suspension or slurry. In this case, theparticles can be isolated by a device such as a magnetic wand.

II. Tracer Particle Dimensions

The present invention provides tracer particles that can be produced toany desired size. In some embodiments, it is desirable to specify aparticular sized particle that is optimized for the various applicationswhere they find utility. The invention provides methods for producingtracer particles of any desired size. For example, particles not largerthan about 400 microns in any one dimension are provided. That is tosay, the particles do not have any dimension larger than about 400microns. Alternatively, particles not larger than about 100 microns, 50microns, 10 microns or 5 microns can also be produced.

As described herein, methods for producing the marked tracer particlescan use traditional photolithography, as well as microcontact printingvariations of photolithography. See EXAMPLES 1, 2 and 3. When thosemethods are used, the final etching step produces an intact sheet ordisk that contains numerous etched copies of the distinguishing mark,but where the intact sheet then needs to be dissociated to produce aplurality of particles, where each particle, or the majority ofparticles, contain at least one copy of the distinguishing mark. Whenusing these photolithography methods, the intact sheet of material canbe either an metal foil sheet, such as an iron sheet, or a sheet of apolymer that is embedded with a magnetic powder, such as an iron powder.

In some aspects, the size of the particle is determined by the use ofmesh screens, as known in the art. This is accomplished by taking theintact printed sheet of material containing multiple copies of theetched mark, and dissociating that material with any suitable device togrind or disintegrate the sheet. In some aspects, any device analogousto a coffee bean grinder can be used, where the material is exposed tospinning blades or any other type of mechanical agitation for an amountof time sufficient to disintegrate the starting material to produce apowder or granular consistency. The powder is then sifted through one,or a combination of, mesh screens having a specified mesh poredimension.

A mesh size designation is the number of openings in one linear inch ofmesh. As the mesh size designation increases, the size of the pores inthe sieving screen decreases. Particles having dimensions smaller thanthe sieve opening size will pass through the mesh, and particles havingdimensions larger than the opening size will be retained and do not passthrough the mesh. By sequentially using two different size screens, apopulation of particles can be isolated having an upper and lower sizelimit.

A number of mesh types and sizes are available from variousmanufacturers. Typical mesh sizing is provided in the table below. Anyof these mesh sizes finds use with the invention to produce tracerparticles having a defined size or size range.

Mesh Sieve Size (number of mesh openings Size of the Mesh Size of theMesh in one linear inch of mesh) Openings (microns) Openings (inches) 30595 0.0232 35 500 0.0197 40 420 0.0165 45 354 0.0138 50 297 0.0117 60250 0.0098 70 210 0.0083 80 177 0.007 100 149 0.0059 120 125 0.0049 140105 0.0041 170 88 0.0035 200 74 0.0029 230 63 0.0024 270 53 0.0021 32544 0.0017 400 37 0.0015

In other embodiments of the invention, the particles are produced usinga reactive plasma etching procedure. See EXAMPLE 4. In some embodiments,when using this procedure, the size of the tracer particles aredetermined by the plasma etch process, where the substrate is etchedwith both the distinguishing mark, as well as etched completely throughthe magnetic polymer substrate layer around its circumference, resultingin the separation of individual particles of fixed length and widthdimensions. In other embodiments of the plasma etching methodology, theplasma etch does not completely penetrate the full thickness of thesubstrate layer. In that case, the plasma etched material can beproduced as a sheet, and that sheet is then processed in a grinder andsifted through one or more mesh screens to produce particles of definedsizes.

The sizes of the tracer particles are customizable. In some aspects,particles having an upper size limit are preferred. For example, theinvention provides particles that do not exceed about 400 microns, orabout 420 microns in any dimension. In other embodiments, the particlesdo not exceed about 350, 300, 200, 100, 80 or 50 microns in anydimension. Still larger particles are also provided. In someembodiments, the present invention is not bounded by an upper limit ofthe particle size. For example, particles can be larger than about 300microns, 400 microns or 500 microns in dimension.

In other preferred embodiments, tracer particle sizes are provided in abounded size range. For example, the invention provides particlepopulations that are between about 250 and 420 microns, or between about250 and 400 microns. Other useful ranges can be, for example, betweenabout 50 and 80, or between about 80 and 100 microns, or between about88 and 105 microns, or between about 74 and 105 microns. Any preferredsize range population can be specified. The size specifications are notlimited to commercially available mesh screen sizes, because the plasmaetching methods of the invention have the ability to produce tracerparticles of any desired size.

The preferred size of the tracer particles of the invention is generallydetermined by the intended use of the particles. In some aspects,particles having sizes not exceeding about 50 microns, or about 80microns, or about 100 microns are generally preferred, and findparticular use in human consumables, such as in pharmaceutical productsand in powder or liquid baby formulas. Larger particles, i.e., particleswith a larger upper size limit, also find use, for example, inapplications that are not as stringent with regard to particle sizelimitations, such as in animal feeds and in explosives. These largerparticles can have sizes that do not exceed, for example, about 200microns, 210 microns, 250 microns, 297 microns, 300 microns, 350microns, 354 microns, 400 microns, 420 microns, 500 microns, or 595microns, and can also be produced as populations of particles havingupper and lower size limits.

III. Tracer Particle Markings

The present invention provides tracer particles that can be produced inany desired size, and further, where the particles contain at least onedistinguishing mark on the surface of the particle. This mark isgenerated by an etching process that can utilize either traditionalphotolithography wet etching, or by a reactive plasma etching process.The size and nature of the etched mark can be optimally selected for theintended application for the tracer particle.

As used herein, the expressions “mark,” “marking,” “distinguishingmark,” “identifying marking” or similar terms refer to a singleintentional mark on the surface of the tracer particle. In someembodiments, the mark is a single alphanumeric character, for example,the letter “M” or the number “5.” As used herein, the expression“maximal dimension of the mark” or a mark not exceeding a fixed size, orsimilar expressions refers to the longest dimension of that onecharacter, for example, the width or the height of the single letter orthe single number.

In some embodiments, the particles of the invention are marked with acombination of characters such as multiple letters and/or numbers thatcan be, for example, an identification or reference number. In otherembodiments, a combination of characters can spell out the name of aproduct or a company. When combinations of alphanumeric characters areused as a mark on a tracer particle of the invention, the expression“maximum size of the marking” refers only to the maximum length or widthof a single letter or number. As used herein, the expression “maximumsize of the marking” and similar expressions does not refer to the fullwidth of the multi-character designation such as in a name of a companyor a multi-character identification number.

Is some embodiments, markings that are not larger than about 40 micronsin any dimension (length or width) are generally used. Markings largerthan about 40 microns in any dimension also find use with the invention.In other aspects, the invention provides smaller markings, for example,markings not larger than about 20 microns, 10 microns, 5 microns, 2microns, or 500 nanometers (i.e., 0.5 microns). Smaller sizes such asnot larger than about 200 nanometers or 100 nanometers are alsoavailable using the methods of the present invention.

As described herein, methods for producing the marked tracer particlescan use traditional photolithography, as well as microcontact printingvariations of photolithography. See EXAMPLES 1, 2 and 3. When thosemethods are used, markings as small as about 10 microns or about 20microns can be produced.

In other embodiments, methods for producing the marked tracer particlesutilize a reactive plasma etching procedure. See EXAMPLE 4. When usingthis procedure, distinguishing markings as small as 500 nanometers (0.5microns), or smaller, can be produced.

A suitable size for the distinguishing marking on the surface of theparticle may be dictated by the preferred size of the tracer particle,or vice versa. For example, if a tracer particle having a maximaldimension of about 100 microns is desired (or in a range of about 50 to80 microns, or about 80 to 100 microns in size, or about 80 to about 150microns in size), a distinguishing mark on the surface of that particlethat is not more than about 0.5 microns to about 20 microns in itslongest dimension would be preferable, so that the mark will fit on theparticle and can be visualized on the particle. Where a particle havingmarkings that are between about 0.5 microns and about 20 microns in sizeis desired, plasma etching methodology as provided herein can be used.In some embodiments, where a particle has markings that are about 0.5microns in size, a particle size of not less than about 5 microns can beused.

If a tracer particle having a maximal dimension of about 400 microns isdesired, a distinguishing mark on the surface of that particle that isnot more than about 40 microns in its longest dimension, or betweenabout 20 microns and 40 microns in size, would be preferable, forexample, as can be produced using microcontact printing methodology asprovided herein.

It is not intended that the invention be limited by the method used toproduce the markings on the surface of the tracer particles. Forexample, in some aspects of the invention, microcontact printingmethodology can be used to produce markings on tracer particles, wherethe microcontact printing is favorably used to produce markingsgenerally larger than about 10 microns in size, for example, betweenabout 10 microns and about 40 microns. In other aspects, plasma etchingis used to produce the tracer particles and the markings on theparticles.

The plasma etching methodology can be favorably used to produce markingson tracer particles, where the markings can be generally smaller thanthe marking produced by microcontact printing. For example, the plasmaetching methodology can be favorably used to produce markings as smallas 20 microns, or as small as 2.0 microns, or as small as 0.5 microns,or in other embodiments, smaller than 0.5 microns.

The markings used on the surface of the tracer particles is not limitedin any regard. Although the use of alphanumeric characters are describedherein, it is not intended that the invention be limited to the use ofalphanumeric characters from the Romance languages alphabet and numbersas distinguishing markings. Any type of intentional mark can be used,such as any type of symbols, lines, arrows, geometric shapes, charactersfrom any type of alphabet (including, e.g., Greek/Latin, Coptic,Cyrillic, Arabic, Hebrew, Chinese), mathematical operators (such assigns for addition, subtraction, multiplication or division), any typeof mathematical notation such as mathematical relationships (equals,less then, greater than, equivalent to), symbols used in calculus anddifferential equations, currency symbols, musical notes, and evenrudimentary representations of easily recognized objects (for example,an umbrella, a car, a person in stick figure representation, a soccerball, a clock, a crescent moon), hieroglyphs, Braille and Morse Code. Insome embodiments, the distinguishing markings on the tracer particlesare non-biologically encoded, and/or are non-naturally occurringmarkings.

In still other embodiments, the distinguishing mark can be notationcorresponding to any type of one-dimensional (linear) bar code or anytype of two-dimensional bar code, also termed a matrix code. A varietyof matrix codes can be used, for example, a QR code or microQR code, a“Data Matrix,” “Aztec Code,” a “MaxiCode,” a “SPARQCode” or a PDF417style code.

In some embodiments, custom tracer particles can be produced containingdistinguishing markings or number/letter combinations that encode aproduct number, a source code, a manufacture date, an expiration date, acode indicating the identity of the bulk material, the name of a companyor the name of a product or a product ingredient, or any other usefulreference information.

In other embodiments, the tracer particles are provided in acombinatorial library. For example, a tracer particle library can bemade from three different premade particles, for example, particlescontaining the characters “A,” “B” and “C.” From this library, a totalof 7 different combinations can be made, which are ABC, AB, AC, BC, Aalone, B alone and C alone. By adding one particle, or combining two orthree particles in a bulk material, seven different unique identifierscan be quickly and cost effectively produced. In the authenticationstep, the person conducting the analysis will look for either one, twoor three different particles in the manufactured item.

IV. Marked Articles

The present invention relates to tracer particles, e.g., magnetic tracerparticles, with at least one identifying marking on at least one surfaceof the particle. Such particles have a wide variety of uses, includingbut not limited to security applications, tags for determining productauthenticity, markers for quantifying bulk material mixing efficiency,measuring/detecting cross contamination and assaying the presence orabsence of micro-ingredients in animal feeds or pet foods.

In some embodiments, marked articles, i.e., tagged products, are formedby the incorporation and dispersing of the tracer particles of theinvention within a flowable dry bulk particulate material at the time ofmanufacture of the article. In some embodiments, the dry particulatematerial is in a powder form or in a granulated form. However, theinvention finds use with any particulate material, including particulatematerials that may fall outside the categories of powders andgranulations. It is not intended that the invention be limited in thisaspect. The present invention finds use with any particulate materials,including but not limited to particulate materials that are described aspowders, agglomerates, granules, pellets or larger flowable bulkmaterials.

Powders are generally dry, bulk solids composed of very fine particlesthat may flow freely when shaken, tilted or poured. Granulars (granularmaterials) typically also have flow properties similar to powders, butare made up of larger (coarser) particles. Granulated forms aregenerally made of particles in the range of about 0.2 mm (200 microns)to 4.0 millimeters in size, while powders are generally made fromparticles that are smaller than granules. The distinctions betweengranulated and powdered materials vary by industry, and are arbitraryfor the purposes of the present invention, and it is not intended thatthe invention be limited in any regard to this aspect.

In some embodiments, the marked articles remain in a flowable dry bulkparticulate state, for example, in infant/baby powder formulas, or drypharmaceutical formulations that will be dispensed in granular or powderform. In other embodiments, the marked articles have lost their flowablebulk particulate form where the tracer particles are ensconced in thesolid article, such as in a solid pharmaceutical tablet. In that case,the tracer particles can be isolated and characterized by first grindingthe solid form to produce a granulated or powdered material, from whichthe tracer particles can be isolated. It is preferable that the groundfrom of the solid be reduced to a particle size of 100 to 150 microns.

In many embodiments, the tracer particles are incorporated into human oranimal consumables (i.e., ingested products) for the purpose ofdetermining product authenticity downstream of the point of manufacture,including such products as human and animal oral pharmaceuticalproducts, animal feed and animal feed premixes, and high value humanconsumables such as infant/baby formulas or other types of infant/babyfoods.

In other embodiments, the tracer particles are incorporated intonon-consumable products, such as plastics and explosive materials.

In embodiments where the tracer particles are incorporated into human oranimal consumables, the tracer particles are manufactured using onlymaterials that are suitable for human or animal consumption. Forexample, when the tracer particles are used to tag non-drug consumables,such as infant formula or other foods, the particles are produced usingonly materials that are generally regarded as safe (GRAS), as known andunderstood in the industry. The labeling of a material as GRAS is adesignation from the United States Food and Drug Administration (USFDA)that a chemical or substance added to food is considered safe byexperts.

If a tracer particle of the invention is produced using only GRASmaterials, then these particles can be safely included within humanconsumables such as pharmaceuticals, nutritional products and foodproducts.

Similar concerns with regard to counterfeiting activity and safeconsumables also exist in the animal feed industry, including livestockfeed and pet foods. Tracer particles of the invention can bemanufactured using materials in compliance with those regulations,thereby making the tracer particles safe for inclusion in formula feedsfor animals, poultry or fish. The feed industry has already permittedthe use of some types of tracing particles in animal feeds to trackfeatures such as microminerals, salts and other drugs. See, for example,Murthy et al., “Evaluation of mixer efficiency test,” Indian J. AnimalNutr., v. 7(2):159 (1990); Calderon et. al., Proceedings, WesternSection, Amer. Soc. of Animal Science, v.51:1 (2000) and Zinn, “A guideto feed mixing,” Research Updates and Reports, Desert Research andExtension Center, Department of Animal Science, Univ. of CaliforniaDavis (1999). For additional description of how tracer particles of theinvention can be used in the animal feed industry, see also, forexample, U.S. Pat. No. 6,406,725 and International Patent ApplicationPublication No. WO2012/103476. In still other embodiments of theinvention as used in the feed industry, whether or not an animal hasconsumed any marked product such as a feed ration or a medication, thesnout of the animal can be examined for the presence or absence of thetracer particle.

One example of feed that can be tagged with a tracer particle of theinvention is a formula feed for poultry, which contains primarily groundcorn and soybean meal, with “macro-minerals” (such as calcium andphosphorous compounds), amino acids, “micro-minerals” (such as zinc andselenium), vitamins, drugs, enzymes, probiotics, mycotoxin binders andother ingredients. Formula feeds can contain hundreds of differentingredients depending upon the species fed and market prices for theingredients. “Least cost” linear programming is commonly used to achievethe desired nutrient profile at the lowest cost. Formula feeds are abulk flow particulate material, and can be tagged with a tracer particleby incorporating the particle into the feed. Alternatively, any onecomponent of the formula feed can be tagged with a tracer particle ofthe invention, so that authenticity of that one component can be testedprior to addition of that component into the formula feed mix.

In other embodiments, whether or not a human or an animal has consumedany marked material containing the tracer particles of the invention canbe determined by examining the fecal matter from that individual, wherethe fecal matter is assayed for the presence or absence of the tracerparticles.

It is not intended that the invention be limited to the tagging offlowable dry bulk particulate material. The tracer particles of theinvention can also be incorporated into liquid bulk materials, orflowable compositions that behave as liquids, such as suspensions,slurries, colloidal solutions and lipids such as oils. In theseembodiments, the tracer particles tag the wet materials and can be usedas authenticity markers. The ability to tag wet materials findsparticular use in high-risk categories of wet materials, such asmedicinal liquid gels, such as gel capsules (e.g., LiquiGels), medicinalliquid-filled capsules (e.g., LiquiCaps®), cough suppressants andexpectorants, premixed liquid infant/baby formulas, or exceptionallyhigh-value foods.

When lipids are used as a liquid bulk material (e.g., a liquidexcipient), lipids that are in a liquid state at room temperature aregenerally preferred. Lipids is a term that includes, for example, oils,fats, shortenings, and waxes, and may be either solid or liquid at roomtemperature, depending on their structure and composition. Lipidsconsist of a diverse group of compounds that are generally soluble inorganic solvents and generally insoluble in water. The term “oils” isusually used to refer to lipids that are liquids at room temperature,while the term “fats” is usually used to refer to lipids that are solidsat normal room temperature.

When a flowable bulk material is used to form a marked product by theaddition of tracer particles of the invention, it is not intended thatthe invention be limited by the nature of the bulk matter. The bulkmatter can be matter of any type or composition, for example, dryparticulate or granular, or liquid. Further, the bulk matter need not beentirely dry or entirely wet. Fat (lipid) compositions in particulateform find use with the invention as bulk material. Particulatecompositions can contain all or some portion of liquid, for example,emulsifying agents, alcohols, or organic acids. Bulk flow particulatematerials can comprise fats, proteinaceous solids (e.g., gelatin andsodium caseinate) or carbohydrate solids (starches and sugars), and allfind use with the invention.

V. Marked Pharmaceutical Products

The present invention provides materials and methods for producingmarked pharmaceutical products. The marked pharmaceutical products areformed by the incorporation of the tracer particles of the inventioninto the bulk phase during pharmaceutical manufacture. The markedpharmaceutical products can be human pharmaceuticals or animalpharmaceuticals.

As used herein, the terms “pharmaceutical,” “pharmaceutical product,”“medicinal product” or “medication” or similar terms refer generally toany manufactured product that is administered to a person or animal thatis intended for use in the medical diagnosis, cure, treatment, orprevention of disease, or to restore, correct or modify anyphysiological functions. A pharmaceutical product can be intended fororal administration, or can be intended for any other type ofadministration, such as parenteral, inhalation, sublingual, topical,rectal or vaginal.

As used generally in the art, and herein consistent with that use, theterm “drug” can refer either to a manufactured pharmaceutical product ormedicinal product, or alternatively, only to the biologically activecomponent that is contained in the pharmaceutical or medicinal product.

Oral medications generally contain a pharmacologically inactive “bulkmaterial” (alternatively termed excipients, bulking agents, fillers ordiluents) in addition to the active ingredient. The bulk materialfacilitates convenient and accurate allocation of the active ingredientand formation of a delivery vehicle, for example, a tablet or capsule.According to the present invention, tracer particles can be added to theexcipient material at the time of drug manufacture, in parallel with theactive ingredient. This process creates a tagged (or marked)pharmaceutical product that can then be tested for the presence orabsence of the tracer particle at any point post-production. Presence ofthe tracer particle in the tested article would confirm an authenticdrug product, and conversely, failure to detect the tracer particle, orinsufficient number of tracer particles, would indicate a fraudulentproduct or product tampering.

In pharmaceutical formulations, a wide variety of dry excipients areknown and used. For example, excipients can include any one orcombinations of materials such as antiadherents (magnesium stearate),adherents, dry binders (cellulose, methyl cellulose,polyvinylpyrrolidone and polyethylene glycol; saccharides and theirderivatives; disaccharides: sucrose, lactose; polysaccharides and theirderivatives: starches, cellulose or modified cellulose such asmicrocrystalline cellulose and cellulose ethers such as hydroxypropylcellulose (HPC); sugar alcohols such as xylitol, sorbitol or maltitol),protein fillers (gelatin), synthetic polymers (polyvinylpyrrolidone(PVP), polyethylene glycol (PEG)), coatings such as tablet coatings(e.g., a cellulose ether hydroxypropyl methylcellulose (HPMC) filmcoating, synthetic polymers, shellac, corn protein zein or otherpolysaccharides, and capsule coatings such as gelatin), enteric coatings(fatty acids, waxes, shellac, plastics, and plant fibers), disintegrants(e.g., crosslinked polymers: crosslinked polyvinylpyrrolidone(crospovidone), crosslinked sodium carboxymethyl cellulose(croscarmellose sodium)), modified starches, fillers/bulkingagents/diluents (e.g., plant cellulose (pure plant filler), dibasiccalcium phosphate, vegetable fats and oils, lactose, sucrose, glucose,mannitol, sorbitol, calcium carbonate, and magnesium stearate),flavorings, colorings, lubricants (talc or silica, and fats, e.g.vegetable stearin, magnesium stearate or stearic acid), glidants,sorbents, preservatives, and sweeteners.

In pharmaceutical formulations, liquid or otherwise wet excipients arealso known and used. The tracer particles of the invention can be addedto these liquid excipients, and used in a manner similar when added to adry bulk material. For example, wet or liquid excipients can include anyone or combinations of materials such as water, solubilisers (sorbitol,dextrose), sweeteners (propylene glycol-glycerine (glycerol)),water-miscible co-solvents (propylene glycol, glycerol, ethanol, lowmolecular weight PEGs), and water-immiscible co-solvents (e.g.,emulsions/microemulsions using fractionated coconut oils).

In some embodiments, for example, in tablet-form pharmaceuticals, thetracer particles need not be incorporated into the bulk material thatcontains the active ingredient. In this case, the tracer particles canbe incorporated into an outer protective coating that covers the tablet.During the manufacture process the outer protective coating is appliedas a bulk material (typically starting as a liquid form), and the tracerparticles are added to that coating bulk form prior to application ontothe uncoated solid tablet. In this case, the presence or absence of thetracer particle is assayed to determine product authenticity nodifferently than if the particle has been incorporated into the bulkmaterial in the interior of the tablet.

In the manufacture of pharmaceuticals, preferred materials are thosematerials that satisfy all food-grade standards and generally mixuniformly into the drug formulation (e.g., any added component mustideally be capable of mixing with the excipient material). Any componentadded to a pharmaceutical formulation must generally be safe, have noundue effect on the biological activity or efficacy of the activeingredient, have no undue effect on stability of the active ingredientor any other component of the formulation, and ideally must notinterfere with any assay for the active ingredient(s), for example, abiochemical assay or an immunoassay.

The invention provides tracer particles that comply with these safetyrequirements. The materials used to manufacture such particles can forexample include only FDA approved GRAS materials, such as FDA approvedferromagnetic materials, for example, iron, iron-nickel allows, gammaferrioxide) and FDA approved polymer binders, for example, bleacheddewaxed shellac, gelatin, derivatives of cellulose such asethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, methyl cellulose; rosin resins such asgum rosins, tall oil rosins, wood rosins and hydrogenated resins. Insome embodiments, the tracer particles are formed from materials thatare intended to degrade or be metabolized after their ingestion.

VI. Use of Tracer Particles in Forensics

In some embodiments, the tracer particles of the invention find use inforensics applications. The inclusion of tracer particles in explosivematerials can allow investigating authorities to identify themanufacturer of explosive bulk materials, and thereby provideinvestigative leads to the identification of the supplier of materialsto make an explosive device, when or where an explosive device was made,or how explosive raw materials were acquired.

The tracer particles of the present invention find use in forensicapplications, for example, by their incorporation into explosivematerials. Such tracer particles can be produced to optimize their usein this type of application. For example, the tracer particles can beexceedingly small (e.g., not more than 100 microns in any dimension), orbe larger in size. The tracer particles are detectable in the rawmaterials prior to ignition/detonation of the explosive material, butmost ideally, tracer particles can be produced that will survivedetonation of the explosive material. For example, particles made ofpure iron or an iron alloy will serve this purpose.

The invention finds use in the tagging of powder/granular forms orliquid forms of explosives, or reagents for producing explosives. Suchmaterials include, but are not limited to, trinitrotoluene (TNT),ammonium nitrate, urea nitrate, nitroglycerin, pentaerythritoltetranitrate (PENT), triacetone-triperoxide (TATP), and hexamethlenetriperoxide diamine (HMTD).

VII. Methods for Tracer Particle Isolation and Detection

The present invention provides methods for the isolation andvisualization of the magnetic tracer particles. Magnetism has been shownto be a rapid, simple and effective means to isolate magnetic particlesfrom either bulk particulate material or from a liquid phase, and isadapted for use in the present invention.

Generally, the magnetic material used in the particles can be the actualsubstrate of the particle, for example, particles of pure iron or aniron alloy, or the magnetic material can be a supplement that is addedto a non-magnetic matrix that forms the physical structure of theparticle. See, for example, U.S. Pat. Nos. 3,469,990; 4,029,820;4,152,271; 4,188,408; and 4,654,165.

In some aspects, the present invention provides ferromagnetic tracerparticles, where the particle is made of iron. In other aspects, theinvention provides ferromagnetic tracer particles that comprise apolymer matrix into which is incorporated a ferromagnetic material, forexample but not limited to, ground iron (powder or granular form). As aresult, either of these types of particles is attracted to magnets(i.e., ceramic magnets, rare-earth magnets or electromagnets), yet willlose its magnetism in the absence of a magnetic field. Therefore, thetracer particles do not clump with each other and will mix uniformlyinto bulk material.

The invention also relates to methods for tracer particle collection andidentification. Generally, the tracer particle needs to be in a flowablestate where it can be isolated away from the bulk material within whichit is contained. In some embodiments, the bulk material is in a freelyflowable form, such as a powder or granular bulk material, or in aliquid bulk material or a liquid-like bulk material. In otherembodiments, the material from which the tracer particles are beingisolated is a solid that has lost its flowable bulk form, such as in asolid pharmaceutical tablet. In that case, the solid form is ground toform a granulated or powdered material, from which the tracer particlescan be magnetically isolated.

The ferromagnetic tracer particles of the invention can be isolated frombulk material using any suitable magnetic separator or magnetic probecontaining a ceramic or rare-earth magnet. For example, a laboratorymagnetic separator such as the MicroTracer, Inc. Rotary Detector™, asdescribed in Eisenberg, “The use of Microtracers™ F (colored uniformlysized iron particles) in coding the presence of coccidiostats in poultryfeeds,” Zootechnica International, Vol. 12, p. 46-50 (December 1998).Any magnetic separator instruments/apparatus for the isolation ofmagnetic particles from dry materials can also be used. For example, amason jar kit can also be used, as described in U.S. Pat. No. 4,152,271.

Alternatively, magnetic probes or magnetic wands can be used to retrievetracer particles that are suspended in a water slurry, or contained inany liquid phase, such as from true solutions, suspensions, colloidalsolutions, or oils. When a magnetic wand is used to collect (isolate)the tracer particles, the wand is generally a hand held magnetic devicecomprising a housing with a magnet placed inside the housing. A handleis mounted to the housing to provide for convenient manipulation of themagnet inside the wand. The wand is exposed to the liquid, then removed,and the particles are collected from the housing of the wand.

Examples describing methodology for the isolation of magnetic particlesare described, for example, in Eisenberg, “The use of Microtracers™ F(colored uniformly sized iron particles) in coding the presence ofcoccidiostats in poultry feeds,” Zootechnica International, Vol. 12, p.46 (December 1998); Eisenberg, “Microtracers' F and their uses inassuring the quality of mixed formula feeds,” Advances in FeedTechnology, Vol. 7, p. 78 (1992); and Eisenberg, “Validatingcross-contamination control,” Feed International, 1 (2006).

Visualization of the tracer particles of the invention is generally bymeans of visual magnification of the magnetically isolated particles.The tracer particles of the invention are too small to be visualizedwithout magnification. The means for visual magnification is notlimiting. Minimal magnification, for example, on the order of about 40×,60× or 100× is sufficient to view the tracer particles and thedistinguishing markings on the surface of the tracer particles. Thisdegree of magnification can be easily obtained with simple visible lightmicroscopy, such as in stereoscopic microscopy (e.g., a dissecting stylemicroscope) that uses incident (reflected) light illumination to viewthe surface of an object. A wide variety of such microscopes can beused, and in some embodiments, the magnifications provided by someportable and/or “pocket” microscopes is sufficient.

Optionally, field-of-view images from the light microscope can becaptured by any light-sensitive means to generate a micrograph. Suchmeans includes photographic film, and more modernly, CMOS andcharge-coupled device (CCD) cameras for the capture of digital images.Purely digital microscopes and imaging equipment systems are alsoavailable where a CCD camera is used to visualize a sample, showing theresulting image directly on a computer screen without the need foreyepieces.

FIG. 7 illustrates some aspects of isolating and detecting theferromagnetic tracer particles of the invention. In this figure, asample is first prepared for analysis. Samples should be in aparticulate state, most preferably in a fine grained powder, or lesspreferably in a granular state. If a sample for analysis is a bulk solid(such as a tablet) or is in a particulate state that is too coarse, thesample must be ground to a finer particulate state.

The particulate samples for analysis are placed into a magneticseparator instrument, for example as shown in the figure, a MicroTracer,Inc. Rotary Detector™ magnetic separator, which provides easy separationof the particles based on their magnetic properties. Other magneticisolation systems can also find use with the invention. In someembodiments, automated apparatus is not required, as simple,unsophisticated methods using a powder slurry (e.g., a powder suspendedin water) and a simple magnet can also be effective at isolating theferromagnetic tracer particles. Also shown in FIG. 7 is a schematic of amagnification device for viewing the ferromagnetic particles, e.g., astereomicroscope (using incident light). The eyepiece, light source,plain glass reflector, condensing system, and the objective areindicated.

VIII. Tracer Particle Secondary Features

The tracer particles of the present invention comprising distinguishingmarkings can be produced containing optional secondary features that aidin detection or analysis of the particles. For example, the particlescan be produced with a coating that aids in their visualization, or avisualization agent can be incorporated into the structure of theparticles. These secondary visualization agents can create an additionaldetectable feature or contribute to combinatorial diversity from asingle ferromagnetic particle.

For example, the particles of the invention can optionally comprise oneor more conventional or fluorescent dyes or pigment, or thermochromicdyes, or any colorimetric compound. When these secondary materials, forexample dyes, are used as coatings on a tracer particle, some of the dyeor other coating material can be lost from the surface of the particledue to abrasion and diffusion in the bulk material; however, qualitativeand quantitative particle recovery is unaffected. In animal feedapplications, essential nutrients or drugs may themselves be used asidentifiable coatings.

In some embodiments, the magnetic tracer particles are isolated frombulk material, but may still be difficult to detect and/or visualize.For example, when tracer particles are isolated from animal feeds, itmay still be difficult to distinguish the tracer particle from “trampiron” common to many types of animal feeds. In that case, it isadvantageous for the tracer particles to contain some secondary featureto facilitate visualization. This can be easily accomplished byincorporating a chromogenic material, a chromophore, a fluorogenicmaterial, a fluorophore, or thermochromic material into the tracerparticle, or as a coating on the tracer particle. This will facilitatethe visualization of the particles, for example, by inducing colordevelopment (as from a water soluble dye) or fluorescence, e.g., whenviewed under UV wavelength light. Using this secondary feature, thetracer particle can be magnetically retrieved and confirmed(authenticated) either with or without viewing the distinguishingmarking that is etched on the particle.

In some embodiments, when dyes are used to optionally coat the tracerparticles, it is preferable that the dyes are certified/approved underthe United States Federal Food, Drug, and Cosmetic Act (FD&C), therebyallowing the use of tracer particles of the invention in human andanimal consumables. See, for example, U.S. Pat. No. 4,654,165. Somenatural food colorings that can be used with the tracer particles of theinvention are generally recognized as safe (GRAS) by the FDA and do notrequire FD&C certification.

Other supplemental features that can be used in conjunction with thetracer particles of the invention include tracer particles that compriselayers displaying different colors in the visible spectrum, orcomponents that emit various spectral signatures when exposed to variousexcitation energy forms; see, for example, U.S. Pat. Nos. 6,647,649 and7,038,766. Tracer particles of the invention can optionally includenaturally occurring biological micromorphological structures that can beidentified using microscopic examination; see, for example, U.S. Pat.Nos. 7,807,468 and 7,964,407. Optionally, the tracer particles can beproduced having unique shapes or outlines that can serve as a secondaryconfirmation feature.

IX. Methods for Tracer Particle Manufacture Using TraditionalPhotolithography

The tracer particles of the invention will be of sufficient technicalcomplexity such that the particles are not easily reproduced or mimickedby counterfeiters. This is accomplished by using micropatterningtechnology to produce particles that have microscale features that willbe very difficult for unsophisticated counterfeiters to reproduce. Onemethod used to produce particles having these features isphotolithography with wet chemical etching.

In some embodiments, the process used to generate the tracer particlesof the invention is traditional photolithography. In traditionalphotolithography, a metal substrate is etched with a defined pattern byuse of a photomask and a light-sensitive photoresist layer. After lightexposure, the photoresist layer is developed, and the resulting patternis then chemically etched into the metallic substrate layer below thephotoresist.

A) Preparation

The metallic material to be etched is typically in the form of a waferor disk. Iron or steel foil is commonly used as a substrate, with athickness between 10 and 100 microns. The disk is cleaned with anorganic solvent, such as ethanol, to make sure that it is free fromdust, dirt or residual oil. The cleaning can include heating, e.g., 100°C., to remove any residual moisture remaining on the disk surface. Aliquid or gaseous “adhesion promoter” can optionally be applied topromote adhesion of the photoresist to the disk.

B) Photoresist Application

The disk is covered with photoresist by spin coating. First, a viscous,liquid solution of photoresist is dispensed onto the disk, and the diskis spun rapidly to produce a uniformly thick layer. Thephotoresist-coated disk is then baked to drive off excess photoresistsolvent.

Resists are generally formulated with polymer loadings of 15 to 30percent by weight with respect to the solvent content of the resistsolution. The viscosity of the solution can be adjusted by varying thepolymer to solvent ratio, thus allowing resists to be formulated forcoating a variety of film thicknesses. In the present invention any ofthe numerous coating methods can be used to apply the resist. The mostcommon are spin coating and dip coating.

A spin coating procedure is used in order to produce a precise, constantthickness of photo-resist across the sample. The speed of the spincoater between 1000 and 7000 RPM is recommended for approximately oneminute. After starting rotation, a few drops of the photo-resistsolution is applied onto the center of the substrate, centrifugal forceseven spread the resist. Variants of this procedure are describedthroughout the literature.

Photo-resists systems consisting of a cresol-formaldehyde novolac resinand diazonaphtoquinone as a photosensitive dissolution inhibitor havereceived a considerable attention due to their high resolution, highthermal stability, and resistance to dry-etching conditions. Ito,“Functional Polymers for Microlithography: Nonamplified ImagingSystems”, In Desk Reference of Functional Polymers: Synthesis andApplications, ed. by R. Arshady, ACS, N.Y. (1996). However, theinvention is not limited in this aspect. Any suitable photoresistmaterial can find use with the invention, including but not limited topoly(methyl methacrylate) (PMMA), poly(methyl glutarimide) (PMGI),phenol formaldehyde resin (DNQ/Novolac), and SU-8.

Soft baking of the photresist layer after application to the disk makesthe photo-resist more sensitive to UV-light by removing the solventcomponent of the photo-resist. A heating for 30-180 seconds at 70-130°C. is recommended for soft baking process. Too short of a prebake willprevent UV-light from reaching the photo-active component due to anexcess of solvent remaining in the photo-resist. Over-baking the samplewill increase the sensitivity to UV light and, in severe cases, maydestroy the photo-active component and reduce the solubility of thephoto-resist in the developer. Because the solvent is mostly removed,the thickness of the photo-resist will usually decrease by about 25%after soft baking.

C) Exposure and Developing

After application and drying, the photoresist is exposed to a definedspecified pattern of light, typically in the ultraviolet spectrum. Theexposure to light causes a chemical change that allows some of thephotoresist to be removed by a subsequent “developer” rinse solution,called by analogy with photographic developer.

The light that reaches the photoresist layer is controlled by aphotomask. In advance of the light exposure, a photomask containingopaque and transparent sections corresponding to the desiredmicropattern is manufactured. Photomasks are generally chrome coatedglass lithographic templates designed to optically transfer patterns towafers or other substrates in order to fabricate planar type devices.Basically, the pattern information is created in a drawing package andstored in a database, reformatted and transferred to a lithography tool,e.g., a laser writer, then printed in a layer of photoresist that iscoated onto the photomask plate. The imaged pattern is next developed toform a template over the opaque chrome and then the chrome is etchedaway where the resist is clear. After the etch process is complete, theremaining photoresist is removed and the plate cleaned.

The finished photomask acts as a patterned light screen when positionedbetween a light source and the photoresist layer. After the photoresistlayer is deposited, the photomask is applied onto the photoresist,followed by light exposure. The mask prevents light from reaching thephotoresist in some areas, and allows light to pass in other areas.Exposure to light occurs through the mask with an optical reduction inthe size of the image. A post-exposure heat treatment is performedimmediately after light exposure and before developing. Masklesslithography projects a precise beam directly onto the photoresist layeron the disk without using a mask, but this technique is not widely usedin commercial processes.

After the photomask is removed, the disk and the photoresist layer asubjected to the develop chemistry. This development solution removesthe portions of the photoresist layer that have not been renderedpermanent by either light exposure, or protection from the lightexposure (depending on the particular photoresist chemistry that isused). The developer chemistry is delivered on a spinner, much like thephotoresist. Historically, developers containing sodium hydroxide (NaOH)were originally used. Modernly, metal-ion-free developers such astetramethylammonium hydroxide (TMAH) are commonly used.

Positive photoresist and negative photoresist protocols are available,according to the action of light and the photoresist chemistry that isused. In a negative working resist, the monomer or oligomer resistmaterial is deposited on the metal surface in the form of a viscousliquid. It is then irradiated through the photomask and polymerization(crosslinking) takes place on the exposed area. The unirradiated liquidmonomer is then washed away in a suitable solvent, and the exposed metalcan be dissolved (completely or partially) in an etching bath. Finally,the remaining protective photoresist polymer layer is removed bychemical or mechanical means and the printed image is ready.

In a positive working resist, the monomer is first polymerized over theentire metal surface, then the protective polymer layer is irradiatedthrough the photomask. In the areas that are irradiated through themask, the polymer is degraded into smaller units and becomes soluble; itcan then be removed by treatment with a suitable solvent and the etchingbath will attack the exposed metal. A variation of this technique can beused for a preparation of integrated circuits one micron in size. Thedescription presented herein uses a negative photoresist, but a positivephotoresist can also be used.

Typically, the substrate of iron or steel foil covered with a layer ofphoto-resist is exposed to UV-light, using the photomask to create bothexposed and unexposed portion of resist. In present invention, a UV-lampwith a maximum of emission at 365 nm was used on this step. The time ofexposure is determined largely by the energy of light (usually between150 and 500 mj/cm²) and can vary from several minutes to several hoursdepending on distance from light source to substrate. It is important tokeep the mask as close to the sample as possible in order to reducedispersion and diffraction of light caused by the gap between the maskand the sample.

The solvents used to develop novolac photo-resists after light exposureare generally aqueous alkaline solutions. The earliest developers usedfor novolac resists were metal hydroxide solutions, such as dilute KOHor NaOH. In cases, when the substrate is more sensitive to metalcontamination, for instance for semiconductor industry, metal containingdevelopers are replaced by organic non-metal developers such assolutions of tetramethyl ammonium hydroxide in water.

The dissolution of novolac resins in aqueous developers is not a simplepolymer dissolution process. In order for the novolac resin to dissolveinto the aqueous solution, hydroxide ions from the solution must firstdeprotonate some of the phenolic sites on the novolac chain. In thisway, dissolution of novolac into aqueous developers is more similar toan etching process, such as metal dissolving in an acidic solution.

In present invention an aqueous solution of sodium hydroxide and/orsodium silicate with concentrations from 0.1% to 10% are used in thedeveloper step. Between 20 and 300 seconds of developer treatment isrecommended depending on the concentration and ambient temperature.

After developing, hard-baking the sample at temperature around 110° C.will strengthen the remaining photo-resist and improve adhesion betweenphoto-resist and the substrate, so that the photo-resist will not beremoved by the etching. In present invention, the hard-baking attemperature between 80° C. and 125° C. for a period of time between 30and 180 seconds is recommended.

D) Wet Etching

In the etching step, a wet chemical agent removes the uppermost layer ofthe metal substrate in the areas of disk that are no longer protected byphotoresist. A variety of wet chemical etching reagents find use withthe invention, for example but not limited to, ferric chloride or ferricsulfate, and mixtures of several components, for example phosphoricacid, nitric acid, acetic acid, and water (4:4:1:1). The invention isnot limited to any particular formulation for wet etching.

The etching intensity is dependent upon the temperature of the reaction,and the concentration of the etching. Conditions must be carefullyselected to avoid the etching mixture attacking the photo-resist,especially at higher temperatures. See, U.S. Pat. No. 6,362,083.

During the chemical etching, the metal layer to be patterned isinevitably subjected to what is called “side etching” by an amountdependent upon the length of chemical etching, resulting in thepatterned metal layer becoming smaller than the pattern of the masklayer by the amount of side etching. The amount of side etching dependsupon the temperature, the flow rate, and other conditions of the etchantused; therefore, it is very difficult to predict the amount of sideetching, and etching conditions may need to be empirically determined.

In some methods of the invention, the aqueous solution of ferric sulfatewith a concentration between 5% and 40% is selected due to the fact thatit is on the list of the FDA approved compounds and provides the fastetching effect. An approximate etch time between 2 and 200 seconds isrecommended, depending on the concentration of etching agent and theambient temperature, which may vary from 15° C. and 60° C.

E) Photoresist Removal

After the photoresist layer is no longer needed, it must be removed fromthe substrate. This usually requires a liquid “resist stripper”, whichchemically alters the resist so that it no longer adheres to thesubstrate. Alternatively, photoresist may be removed by a plasmacontaining oxygen, which oxidizes it. This process is called ashing, andresembles dry etching.

This traditional photolithography procedure is shown generally in FIGS.1A and 1B. FIG. 1A illustrates a positive working photoresist. In thatfigure, a metal substrate (s), for example iron foil, is deposited on anoptional insulator base (b). This metal substrate (s) is covered by anoverlying photoresist layer (r). Irradiation of the resist through aphotomask (m) results in photo-induced polymer destruction in areas ofthe photoresist layer that are exposed to the incident irradiation. Thisis followed by the developing rinse to remove the irradiated photoresistmaterial and subsequent wet etching of the exposed metal substrate, toproduce the final etched product.

FIG. 1B illustrates a negative working photoresist. In that figure, ametal substrate (s) is optionally deposited on an optional insulatorbase (b). This metal substrate (s) is covered by an overlyingphotoresist layer (r). Irradiation of the resist through a photomask (m)results in photo-induced crosslinking in areas of the photoresist layerthat are exposed to the incident irradiation. This is followed by thedeveloping rinse to remove the non-irradiated photoresist material andsubsequent wet etching of the metal substrate surfaces that are revealedby removal of the non-crosslinked photoresist material, to produce thefinal etched product.

To produce the tracer particles of the invention, the engraved diskcontaining many images of the distinguishing mark is disintegrated intofragments of any desired size or size range, where each particle ornearly every particle contains at least one copy of the distinguishingmark.

X. Methods for Tracer Particle Manufacture Using Microcontact Printing

In one aspect of the invention, a microcontact printing procedure isused to produce distinguishing markings on the surface of the tracerparticles. Microcontact printing initially uses the steps of traditionalphotolithography to first produce an etched “master” plate, which can bemanufactured from metals such as iron or steel, or can be manufacturedfrom silicone, where the master plate contains reiterations of thedesired micrometer-scale or nanometer-scale patterning. That masterplate is then used to from a reusable elastomeric stamp containing aninverted image of the desired microengraved pattern. The stamp is thenused to generate many copies of the micropattern onto either a metallicsubstrate or a polymer substrate. Microcontact printing may incorporatetraditional photolithography for making the master plate form, which canbe a silicone master plate or a metal-based master plate. Becausemicrocontact printing incorporates elastomeric materials, it issometimes termed a modified version of soft lithography.

The original process of microcontact printing was proposed by Kumar andWhitesides in 1993. Kumar and Whitesides, Appl. Phys. Lett., v.63, p.2002 (1993). Modernly, technical improvements of the basic protocol havebeen made, including reducing stamp swelling during the “inking” processby using a “stamp pad” method, and the use of elastomer soaked in ink tolocalize the inking to the stamp corrugations. See, e.g., Quist et al.,Anal. Bioanal. Chem., v.381, 591 (2005) and Libioulle et al., Langmuir,v.15, 300 (1999).

The disclosure herein described the use of elastomericpolydimethylsiloxane (PDMS) to form the stamp that is cast from themaster plate. PDMS is commonly used to produce microcontact printingstamps because the product is optically clear, inert, non-toxic andnon-flammable. However, it is not intended that the invention be limitedto the use of PDMS to form a stamp, as other materials to form contractprinting stamps are known to one of skill in the art, and can beselected in view of the intended use of the stamp.

In microcontact printing, the stamp thus produced from the master (incombination with a suitable ink) can be used in two different etchingprotocols. First, the stamp can be used to chemically etch a metalsubstrate, such as an iron foil. In that case, the ink that is used isan acid, such as hydrochloric acid (HCl) based solutions. Although theuse of iron foil is described herein, it is not intended that theinvention be limited to the use of iron foil, as other magnetic metalsand metal alloys can also be used as substrate materials to generate thetracer particles of the invention, for example but not limited toiron-nickel and iron-cobalt, all of which find use with the invention.Similarly, other acid-based etch solutions can be used to etch the metalsubstrate, including but not limited to nitric acid, phosphoric acid,acetic acid, and mixtures thereof.

In a second methodology, the stamp can alternatively be used tochemically etch an organic polymer layer that contains iron or otherferromagnetic additive. As used herein, the expression “polymers findinguse with the invention” or similar constructions refer to polymerbinders, where polymerization or crosslinking of the polymer can providea cohesive matrix from which tracer particles can be formed, andfurther, where the matrix is sufficiently dense to sequester or bindadditional components that are present at the time of formation (i.e.,at the time of polymerization or crosslinking). For example, polymersthat can sequester a magnetic powder additive can be used to form thetracer particles of the invention.

When an organic polymer layer is used in the microcontact printingprocess, the ink that is used is an organic solvent like ethanol, whichpartly dissolves (swells) the polymer in the areas of the polymer thatcome into contact with the stamp. Although the use of ETHOCEL™ethylcellulose is described herein as a polymer substrate, it is notintended that the invention be limited to the use of that polymer, as awide range of other polymer materials are known to one of skill in theart and can be used with the invention, and can be optimally selected inview of the intended use of the tracer particles to be produced. Forexample, polymers (i.e., polymer binders) can be FDA approved polymerbinders, for example but not limited to, shellac, gelatin, derivativesof cellulose such as ethylcellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methylcellulose; rosin resins such as gum rosins, tall oil rosins, wood rosinsand hydrogenated resins. Similarly, it is not intended that theinvention be limited to the use ethanol as the etching material.

FIG. 2 shows a schematic representation of formation of a stamp andsubsequent substrate etching in microcontact printing. An elastomericmaterial such as polydimethylsiloxane (PDMS) is applied to a masterdesign template (step A) and allowed to cure (step B), thereby forming aremovable stamp. After peeling the stamp away from the master, ink isapplied to the stamp (step C). The ink is then transferred to asubstrate by placing the ink-containing stamp into contact with thesubstrate (step D), i.e., stamping the substrate. After removal of thestamp, the desired micropattern is etched into the underlying substrateby the etching action of the ink (step E). In the case where thesubstrate is a metal, an acid-based ink can be used. In the case wherethe substrate is a polymer, such as a plastic, an organic polymer, or afood-grade polymer, an organic solvent-based ink can be used.

The microcontact printing process is clearly contrasted with traditionalphotolithography. In traditional photolithography, there is nointermediate stamp step, and the etching substrate is always a metallicsubstrate. Further, in traditional photolithography, the photoresistlayer is applied directly to the substrate material that will producethe end product. In contrast, in microcontact printing, a photoresistprocess is only used in the construction of the master plate, and aphotoresist is not used in production of the etched final product.

XI. Methods for Tracer Particle Manufacture Using Plasma Etching

The present invention provides methods for producing the magnetic tracerparticles of the invention, where the methods utilize reactive plasmaetching to produce the distinguishing markings on the surface of thetracer particles, as well as generating particles of predetermineddefined sizes, and where the particles are separated from each other.This methodology can incorporate photolithography as one or moreintermediate steps during preparation of the tracer particles.

Plasma etching generally follows the strategy of photolithography, withthe important distinction of the etching process is delivered.Traditional photolithography uses wet chemical etching, where theprocess that removes either the metal or polymer substrate material isin a liquid phase. In contrast, the plasma etching process is a drychemical etching, where the etching reagents are components of areactive gas or plasma, and where the etching reaction consumes thesubstrate material by generating only volatile etching byproducts.Plasma etching includes techniques such as physical sputtering, ion beammilling and reactive ion etching.

Like wet chemical etching, dry etching also follows the resist photomaskpatterns on a wafer or disk, i.e., the process only etches awaymaterials that are not covered by mask material (and are thereforeexposed to the etching species), while leaving areas protected andcovered by the photomask almost (but not perfectly) intact. These masksare deposited on the wafer by an earlier wafer fabrication step,consistent with traditional photolithography.

Plasma dry etching consists essentially of the following steps: (1)generation of reactive species in a plasma; (2) transport of thesespecies to the surface of the material being etched; (3) interaction ofthese species with the surface; (4) occurrence of interactions betweenthe species and the material being etched, forming volatile byproducts;(5) transport of the byproducts from the surface; and (6) transport ofthe desorbed byproducts into the bulk of the gas. Plasma etching can beused to produce patterned substrates (i.e., the tracer particles of theinvention) that are either metallic, such as iron foil, or comprise apolymer, such as an organic polymer, where the polymer further includesiron or another magnetic additive.

As used herein, plasma etching is used to selectively remove materialfrom a polymer stack. As used herein, the plasma etching step is alwayspreceded by a traditional photolithography step. The plasma etchingprocess of the invention can produce distinguishing markings having anydesired dimensions, although most typically, the plasma etching methodsare capable of producing markings on tracer particles that are smaller(i.e., have higher resolution) than the markings produced bymicrocontact printing methods of the invention. In some embodiments, themarkings, for example alphanumeric characters, on the tracer particlesthat are produced by plasma etching are generally in the range of 2microns to 20 microns in height. However, smaller characters, such ascharacters as small as 0.5 microns (500 nanometers), 100 nanometers, 65nanometers or 50 nanometers are also producible with the plasma etchingmethods of the invention. Distinguishing markings larger than about 20microns on the surface of tracer particles can also be produced by theplasma etching methods of the invention.

A schematic showing the general methodology for plasma etching togenerate tracer particles of the invention is shown in FIG. 3. Thisprocess as shown in FIG. 3 is analogous to the plasma etch process thathas broad application in the engineering of microelectronics in thesemiconductor industry. For example, plasma etching is used to producemetallic connections between electronic components (such as resistors,capacitors and integrated circuits). This is accomplished by theselective etching of an insulating silicon oxide layer, followed byfilling the gaps in the silicon oxide with a metal such as copper. Thesilicon oxide layer is protected by a resist, which is a polymer,deposited in such a way that it protects selected portions of thesilicon oxide during exposure to a reactive plasma. The lines createdwhen the silicon oxide is etched are later filled with metal and becomethe basis for creating circuits. See, e.g., U.S. Pat. No. 6,140,226, andSuppan, Chemistry and Light, Springer Press, The Royal Society ofChemistry, Cambridge, UK (1994).

The plasma etching process generally starts similarly to traditionalphotolithography, where materials are deposited as layers onto thesurface of a substrate to be etched, followed by light exposure,photolithography, and finally the dry plasma etching to selectivelyremove material.

A) Deposition of a Silicon Oxide Liftoff Layer

The first step is to grow or deposit a layer of silicon oxide on a cleanwafer. The purpose of this layer of silicon oxide is to act as a liftofflayer when the etching process is complete and the tracer particles canbe conveniently released from the wafer. This layer serves to reduce therisk of stiction when removing the polymer particles from the wafer atthe end of the process. This step may be considered optional, thoughemploying it typically increases the breadth of the process window.

There are many methods of depositing silicon oxide onto a wafer,including thermal oxidation of silicon, plasma oxidation of silicon,deposition via PECVD (Plasma Enhanced Chemical Vapor Deposition) andapplication of a spin-on oxide. For this process, the preferred methodis application of a spin-on oxide (Holmes et al., Appl. Opt., v.32, p.4916 (1993)), although any suitable method finds use with the invention.

B) Application of the Magnetic Polymer Layer

Spin-coating is a commonly used method of applying a soluble material toa flat surface. Typically, a homogeneous solution of a polymer isprepared, and a few drops of the solution are placed at the center of asilicon wafer. The wafer is then spun at a predetermined speed untilcentrifugal force has removed the excess solution from the wafer. Spincoating was selected as the preferred method for coating the wafer witha magnetically active polymer substrate, in view of the wideavailability of spin-coating equipment and reagents, and the welldocumented methods for spin coating taking into account materialviscosity, density, solvent characteristics and layer characteristics.

C) Application of a Dielectric Hardmask

After the magnetically active polymer layer has been added to the wafer,a dielectric hardmask is deposited. The dielectric hardmask has twoimportant functions. First, it separates the FDA-approved polymer fromthe photoresist that will later be used in patterning of the wafer, andsecond, it generates a chemically orthogonal system for etching. Variousdielectric materials can be used, and the dielectric can be deposited ina variety of ways, all of which find use with the invention. Thesimplest material to use is silicon oxide and the simplest method ofdeposition is spin-coating from a spin-on-oxide.

Use of a dielectric hardmask is optional; the material can bemanufactured without this step, albeit in a more complex and error-pronemanner. It is important to note that the density of the dielectric layeris less important in this application than in typical semiconductorelectronic applications. Even a dielectric layer that is not dense andthat contains pinholes or other flaws can be used for this application.

D) Application of Photoresist

A wide variety of photoresists are known to one of skill in the art, anyof which can be used with the invention. In one embodiment, the industrystandard SU-8. Lorenz et al., J. Micromech. Microeng., v.7, p. 121(1997). Photoresist material is sensitive to light in definedwavelengths, depending on the material that is used. Because SU-8 isphotosensitive, all manipulations that involve this material must takeplace in a room illuminated with light in the yellow portion of thevisible spectrum.

E) Photolithography

In order to prepare the wafer for etching, the photoresist must first beselectively exposed to patterned light through a photomask. Light ofappropriate wavelength is passed through the mask to selectively exposeportions of photoresist. After exposure, the photoresist is rinsed witha developer and baked.

F) Etching of the Dielectric Hardmask

Once photolithography is complete, the oxide hardmask and the magneticsubstrate layer can then be etched. Both etching steps take place in aplasma etch tool. Most common plasma etch tools use a 13.56 MHzcapacitively coupled plasma, though tools which use 2 MHz, 60 MHz, 120MHz, 2.4 GHz or any other frequency of RF can also be used. Theinvention is not limited in this aspect.

The dielectric hardmask is etched first. In this step, the dielectric(i.e. silicon oxide) is the target material and the photoresist is themask. Selectivity of approximately 1:1 to 3:1 is expected. A widevariety of fluorine-based plasmas can be used to etch silicon oxide; insome embodiments, a perfluoromethane (CF₄)/argon system is used becauseof its simplicity and ease of characterization. If an increased etchrate is desired, a small amount of oxygen or nitrogen can be added tothe gas mixture.

G) Etching of the Magnetic Polymer Substrate

Once the oxide hardmask has been etched, the magnetic polymer is then beetched. In this step, the oxide hardmask is the mask and the magneticpolymer is the target layer. Selectivity of over 10:1 is expected.Several different gas mixtures can be used to etch organic polymers; insome embodiments, oxygen or a mixture of oxygen and argon are used toperform the main etch. If the material etches too quickly with thisplasma, or if the etch is too isotropic, carbonyl sulfide can be addedto slow the process and limit etching in the horizontal direction. Amixture of hydrogen and nitrogen (or just a short treatment ofadditional oxygen) can be used to clean the edges of the polymer aftercarbonyl sulfide has been applied. Nitrogen can also be added to theoxygen main etch if this process needs to be slowed.

This plasma etching process produces the engraving that adds thedistinguishing marks to the polymer substrate, as well as cutting clearthrough the full polymer depth in defined patterns in order to separatethe individual tracer particles from each other.

In other embodiments, reactive plasma etching is used to produce adistinguishing mark without etching completely through the magneticpolymer substrate layer, and in that embodiment, the polymer materialremains in a sheet at the end of the etching process. In those methods,the tracer particles are generated by grinding the sheet and sizesorting the resulting particles, as described herein. In still otherembodiments, the plasma etching can be used to etch completely throughthe magnetic layer without producing a distinguishing mark.

H) Release of Magnetic Polymer Particles

Once the polymer substrate etching step is complete, the marked tracerparticles of the invention have been produced. The only remaining stepis to release and collect those particles from the silicon wafersupport. To accomplish this, a wet etch can be used to dissolve theremaining silicon oxide hardmask and the oxide release layer. Thisreleasing process should take place in a vessel of a wet etch solutionsuch as NH₄F/H₂O or KOH/H₂O.

To collect the particles, a strong magnet should be fitted with aplastic bag, then placed into the solution above the wafer. Once thehardmask and release layer have been removed, the particles can floatfree of the wafer and to the magnet. After the tracer particles havebeen collected, they should be rinsed in deionized water or anotherappropriate solvent and dried.

EXAMPLES

The following examples are offered to illustrate, but not limit, theclaimed invention. It is understood that various modifications of minornature or substitutions with substantially similar reagents orcomponents will be recognizable to persons skilled in the art, and thesemodifications or substitutions are intended to be included within thespirit and purview of this application and within the scope of theclaimed invention.

Example 1 Protocol for the Production of Tracer Particles UsingTraditional Photolithography

This example describes a method that was used to produce tracerparticles using traditional photolithography and wet etching.

A) Preparation

The stainless steel foil Blue Tempered Shum Stock (Spring Steel C-1095with a thickness of 0.002 inch (51 micron); Lyon Industries) was cleanedwith ethanol, to make sure that it is free from dust, dirt or residualoil. The washed foil was subjected to baking at 100° C. for 4 hrs toensure that any residual water on the sample evaporates out.

B) Photoresist Application

Novolac resin DNQ-novolac was dissolved in PGMEA (propyleneglycol methylether acetate) at a concentration 15% containing diazonaphthoquinone(DNQ) to form the photoresist material. Spin coating was used to producea constant thickness of photo-resist across the steel foil substrate ata speed of about 1200 RPM for approximately 1 minute. After startingrotation, a few drops of the photo-resist solution is applied onto thecenter of the substrate, and centrifugal forces evenly spread theresist. Soft baking to make the photo-resist more sensitive to UV-lightby removing the solvent component of the photo-resist was performed byheating for 40 seconds at a temperature of 90° C.

C) Exposure and Developing

The stainless steel foil substrate covered with a layer of photo-resistwas exposed to UV-light, using a photomask to create both exposed andunexposed portions of resist. A UV-lamp with a maximum emission at 365nm (Black Light, Model ZB-100F; Magnaflux, Inc.) with an energy of lightapproximately 150 mj/cm²) was applied for 6 hours, with the mask asclose to the sample as possible in order to reduce dispersion anddiffraction of light caused by the gap between the mask and the sample.

The developing novolac photo-resist was performed using 10% sodiumhydroxide solution in deionized water for approximately 60-80 seconds.The sample was then hard-baked at a temperature of about 110° C. for 180seconds in order to strengthening the remaining photo-resist and improveadhesion between the photo-resist and the substrate.

D) Wet Etching

Etching was conducted using an aqueous solution of ferric sulfate at aconcentration of about 20%, with an exposure time of about 150 secondsat room temperature or alternatively for 80 seconds at 40° C.

E) Photoresist Removal

The residual layer of photo-resist was removed from the stainless steelfoil substrate by treating with cyclohexanone at 45-50° C. for 10minutes, followed by treatment with acetone for 10 minutes at ambienttemperature, followed by a final rinse with ethanol and dried at ambienttemperature.

FIG. 4 shows an photomicrograph of the intact iron foil at magnificationof 60×. The height of the letters in “MICRO TRACERS” is approximately 40microns.

E) Grinding

To produce tracer particles, the engraved foil was disintegrated intofragments using a coffee grinder, then consecutively sifted through twoscreens, one with size 40 mesh and other with size +60 mesh, therebyproducing particles having a size range of approximately 250 microns toapproximately 420 microns.

Example 2 Protocol for the Production of Polymer Tracer Particles UsingMicrocontact Printing

This example describes a method for producing polymer-based tracerparticles using microcontact printing, that is, by first producing amaster template, from which is formed a stamp that is then used to imagea polymer substrate that will form the tracer particles.Photolithography principles are used in the construction of the masterplate.

A) Producing A Silicone Master Plate

Traditional photolithography with a laser-produced photomask were usedto generate a silicone master plate containing repeating patterns of themicroetched mark, in this case, the word “MICROTRACERS.”

B) Producing A PDMS Stamp

To make a PDMS stamp, the silicone master form with the micrometer-scalepattern of the work “MICROTRACERS” was used as a template. A mixture ofliquid polydimethylsiloxane and SYLGARD® 184 silicone elastomer curingagent (Dow Corning), in a ratio of 10:1 was prepared, and degassed undervacuum for 20 to 30 minutes. The resulting solution was poured over thesilicone master in a plastic petri dish.

The PDMS mixture was left in contact with the master pattern to cure fortwo hours at 65° C. At the end of that time, the resulting elastomericmold is carefully peeled apart from the master form. This resultingflexible stamp produced a raised relief of the desired micropatterningimage.

C) Preparing an Ethocel™ Polymer Film Containing Iron Powder

Titanium dioxide (TiO₂) powder (2.0 grams, pre-sifted) was dispersed inethanol (52 ml) by magnetically stirring at room temperature for 15 min.The prepared dispersion was strained through a screen (#140 mesh size)to remove large TiO₂ particles. After returning to the magnetic heatedstir plate, the dispersion was stirred and heated to 40 to 50° C.

Next, 6.0 g of ETHOCEL™ ethylcellulose polymer (Dow Chemical Company)was added to the dispersion, taking care to avoid agitating thedispersion or forming any clumps. After all of the ETHOCEL™ isdissolved, 19.0 g of the prepared solution was transferred to a beaker.While continuously stirring, electrolytic iron powder (5% by weight,powder size below 325 mesh) was added.

The uniform dispersion was added to a 100 mm diameter disposable Petridish and place into vacuum chamber. Air bubbles were removed bysubjecting the polymer solution to a low vacuum. Any remaining solventwas allow to evaporate in a refrigerator (5 to 8° C.) for 48 hours.

D) Stamping the Ethocel™ Film Substrate

An additional suspension of TiO₂ (0.5 g) and ethanol (10 mL) wasprepared by vigorously stirring components for 15 minutes. The surfaceof the ETHOCEL™ ethylcellulose polymer film was moisturized with the newsuspension and dried at room temperature. Before stamping, the PDMSstamp was moisturized with ethanol. The ETHOCEL™ film was stamped byplacing the PDMS stamp into contact with the surface of the film using aforce of about 1.5 to 2 kg/cm² of pressure for 15 minutes. The value offorce applied was calculated by determining the weight of the stampingdevice (4.5 to 6 kg) divided by the surface area of the stamp (3 cm²).

This stamping with ethanol partially dissolved (swelled) the polymer inthe area of contact. The polymer film was then thermo-treat (i.e.ironed) between two metal sheets, then the stamping procedure wasrepeated on the opposite side of the polymer film.

E) Ethocel™ Film Grinding to Produce Particles

The printed areas of ETHOCEL™ polymer film were cut out and ground usinga hand-held coffee bean grinder. The film was ground to a powder-likeconsistency. That powder was then consecutively sifted through 40 and 70mesh-size screens, in that order, thereby generating a population ofETHOCEL™ film fragments ranging in size between about 210 and 420microns.

The resulting magnetic particles were observed under a conventionalOLYMPUS® CH2 Series optical microscope with magnification of 60×. Afield of view was captured in the photomicrograph shown in FIG. 6. Theheight of the letters forming “MICROTRACERS” is approximately 40microns.

Example 3 Protocol for the Production of Metal Tracer Particles UsingMicrocontact Printing

This example describes a method for producing iron tracer particlesusing microcontact printing, that is, by first producing a mastertemplate, from which is formed a stamp that is then used to image aniron foil substrate that will form the tracer particles.Photolithography principles are used in the construction of the masterplate.

A silicone master plate and a corresponding flexible PDMS stamp wereproduced as described above in EXAMPLE 2. In this case, the siliconemaster plate and PDMS stamp contained the test symbols “ABC”.

After the PDMS stamp was created, it was coated with a protective “ink”comprising a light wax such as petroleum, paraffin or bees wax at aconcentration of about 0.1% to 1.0%, dissolved in naphtha. A variety ofother ink formulations also exist and can find use with the invention.The concentrations of those light waxes was optimized empirically.

An iron foil having thickness of about 50 microns was laid flat on aclean surface. The PDMS stamp was moisturized with the ink formulationand brought into contact with the iron foil for about 15-20 seconds,then removed.

After application of the protective ink, the stamped iron sheet was thensubmerged in an etching bath comprising ferric sulfate in aconcentration of 15%, although concentrations between 5% and 40% can beused in order to optimize the etching process. The etching will removeiron from the sheet in any location that is not covered by wax, therebycreating a raised relief corresponding to the desired pattern. Theetching reaction was stopped by removing the plate from the etching bathand rinsing with water, and then dried.

In some embodiments, ferric sulfate is a preferred etching reagent formetal substrates because it is FDA approved for the animal feed industryand, depending on the concentration of the acid and the temperature ofthe reaction (which may vary between 15° C. and 60° C.), the etchingeffect is achieved in less than three minutes. Furthermore, only wateris required for cleanup of the acid solution.

Although ferric sulfate is described herein, it is not intended that theinvention be limited to the use of ferric sulfate. Other etching acidscan also be used, such as nitric acid, phosphoric acid, acetic acid, andtheir mixtures thereof, and the concentrations of those acids can alsobe optimized, as known to one of skill in the art. Concentrations of theetching acid can be optimized and may potentially be in a concentrationranging anywhere from 0.1 milliMolar (0.1 mM) to 1.0 Molar (1.0 M).

The resulting intact stamped and etched iron foil was visualized using astereomicroscope using approximately 60× magnification. A field of viewwas captured in a photomicrograph, as shown in FIG. 5. Each of the A, Band C characters in the field of view is approximately 40 microns inheight.

After production of the etched metal foil sheets, the sheets can beground, as described in EXAMPLE 2, to produce the tracer particles ofthe invention.

Example 4 Protocol for the Production of Tracer Particles Using PlasmaEtching

This example describes methods for producing tracer particles usingreactive plasma etching, where exposure to reactive gas plasmaaccomplishes both the etching of the distinguishing markings on theparticles, as well as generating particles of predetermined definedsizes, and where the particles are separated from each other. Thismethodology incorporates photolithography as one or more intermediatesteps during preparation of the particle substrate. A schematic showingthe general methodology for plasma etching to generate tracer particlesis shown in FIG. 3.

A) Deposition of the Material Stack on the Wafer

A spin-on oxide layer is used to promote liftoff of the finishedparticles. To manufacture this layer, a clean silicon substrate isplaced on a spin coater. A few milliliters of spin-on-oxide solution areput on the wafer, until about 80% of the surface of the wafer is coatedwith fluid. The spin-coater is then ramped to 500 RPM at a rate of 100RPM/second and then ramped to 3,000 RPM at a rate of 300 RPM/second. Thespeed of 3000 RPM is held for ten seconds.

After the layer has been spun onto the wafer, it must be annealed to thesilicon substrate. The wafer containing the coating is placed on a hotplate at a temperature of 200° C. for 15 minutes. Then, with the waferremaining on the hot plate, the temperature of the hot plate isincreased to 300° C. The hot plate is maintained at 300° C. for 15minutes and then allowed to cool to room temperature.

The magnetic polymer layer is then applied to the wafer. A wafer with asilicon oxide liftoff layer already deposited is placed on aspin-coater. About 20 milliliters of polymer solution is dropped ontothe center of the wafer and the spin-coater is ramped to 500 RPM at arate of 100 RPM/second, and then ramped again to 2,000 RPM at a rate of300 RPM/second. The speed of 2,000 RPM is held for 30 seconds.

Next, a layer of silicon oxide is deposited to act as a hardmask duringthe etch process. A clean silicon substrate is placed on a spin coater.A few milliliters of spin-on-oxide solution are put on the wafer, untilabout 80% of the surface of the wafer is coated with fluid. Thespin-coater is then ramped to 500 RPM at a rate of 100 RPM/second andthen ramped to 3,000 RPM at a rate of 300 RPM/second. The speed of 3000RPM is maintained for ten seconds.

After the layer has been spun, it must be annealed. The wafer is placedon a hot plate at a temperature of 200° C. for 15 minutes, and thenallowed to cool.

The final layer to be added to the material stack is the photoresistlayer. This protocol uses SU8-2 photoresist. A wafer that has recentlycompleted the spin-on hardmask step is placed on a spin-coater. Eight(8) mL of photoresist solution are dropped onto the center of the wafer.The spin-coater is then ramped to 500 RPM at a rate of 100 RPM/secondand then ramped to 3,000 RPM at a rate of 300 RPM/second. The speed of3000 RPM is held for 60 seconds.

After spin-coating, the wafer is baked. The wafer is put on a hot plateat a temperature of 65° C. for three minutes. The temperature of the hotplate is then increased to 95° C. and the wafer is allowed to bake foran additional three minutes

B) Etching and Microengraving to Produce Tracer Particles

The first step in etching the tracer particles is photolithography. Inthis example, a contact mask is used in the photolithography. The maskis placed on top of the wafer. Care is taken to ensure that there are noair bubbles or gaps between the mask and the wafer. The mask should beplaced with the printed side making contact with the wafer.

The wafer is placed under a lamp which emits light at 365 nm. A 350 nmhigh-pass filter is placed between the lamp and the wafer, and the lampis turned on for about 10 seconds.

The wafer is developed by placing it in a tub of development solutionand agitating it for three minutes. A sonication tool may optionally beused to aid in agitation. The wafer is then dipped into a second tub offresh development solution and rinsed in isopropanol. If development isincomplete, the isopropanol becomes milky in appearance and the wafer isagain placed in the tub of development solution and agitated. Afterdevelopment is complete, the wafer is dried in a stream of nitrogen orcompressed air.

A post-exposure bake is used to complete cross-linking of the exposedareas. The wafer is placed on a hot plate, the temperature of the hotplate is increased to 95° C., and the wafer is allowed to remain attemperature for three minutes.

After photolithography is complete, the dielectric hardmask must beetched. This step takes place in a plasma etch chamber. Typically, thewafer is placed in an etch chamber and the vacuum engaged. The pressurein the chamber is allowed to reach 5 mTorr or less before moving on tothe next step.

To initiate a plasma reaction and begin the etch process, argon isflowed into the chamber and the throttle valve set so that the pressurein the chamber is 50 millitorr. The RF generator is turned on with apower setpoint of 100 W to strike a plasma. With the plasma remainingon, the gas mixture is changed from 100% Ar to 80% CF₄/20% Ar. The gatevalve and total flow are adjusted to maintain a pressure of 50 millitorrin the chamber.

The main portion of the etch process uses a higher RF power than thestriking portion. The RF power is increased to 200 W and the process isallowed to operate for 120 seconds, or the etch time determined throughprevious experiments.

Once the dielectric hardmask has been etched, the next step is to etchthe magnetic polymer. A 50/50 mixture of argon and oxygen is flowed intothe chamber and the throttle valve adjusted such that the pressure inthe chamber is 50 mT. The RF generator is activated with a set point of100 W to strike a plasma.

The main portion of the etch process uses oxygen to oxidize targetedportions of the polymer. The gas mixture is changed from 50/50 Ar/O₂ to95% oxygen/5% carbonyl sulfide and the gate valve and total flowadjusted so that the pressure in the chamber is 20 mT. The plasma shouldremain on throughout these changes.

Once the gas flows have stabilized, the RF power setpoint is increasedto 300 W. The process is allowed to operate for one minute for eachthree microns of thickness of the magnetic polymer. A sulfur-free gasmixture is used in the final etch step to clean up the edges of thepolymer. The gas mixture is changed from 95%/5% oxygen/carbonyl sulfideto 50/50 hydrogen/nitrogen, and the process allowed to operate for 30seconds. After the proceeding plasma etch steps are complete, theparticles have been etched and engraved.

The particles must now be collected, rinsed, dried and stored. Thedielectric hardmask and liftoff layer surround the tracer particles likebread in a sandwich. To release the particles, the liftoff and hardmasklayers are etched away. To accomplish this, the wafer is placed in aplastic tub with a magnet covered by a plastic bag, the magnetpositioned approximately five centimeters above the wafer. A pre-mixed1M solution of ammonium fluoride is poured into in the tub so that itcovers the wafer and the bottom of the magnet. The wafer is thenagitated to speed lift-off of the particles. The particles are rinsedwith water and then dried.

Example 5 Production of a Pharmaceutical Product Comprising TracerParticles and Retrieving the Tracer Particles from the Tablet

This example describes the production of a pharmaceutical product thatincorporates tracer particles. This example uses aspirin to illustratethe principles of how the tracer particles of the invention can beincorporated into any hypothetical drug formulation where the bulk flowmaterials containing the tracer particles are transformed in theproduction process to yield a solid formulation such as a tablet. Thisexample also serves to illustrate how magnetic particles can beretrieved, visualized and quantitated from solid pharmaceuticalformations, such as tablets.

A) Production of Tracer Particles

A dispersion is made with ethanol (52 ml), ETHOCEL™ ethylcellulose (6.0g), TiO₂ powder (0.5 g) and iron powder (0.3 g, powder size between 1and 6 micron). Thiamine hydrochloride (0.06 g) is also added andstirring occurs at room temperature for 15 minutes. The dispersion isthen used to make 100×100×80 micron ferromagnetic tracer particles withalphanumeric markings 15 microns in height (according to the descriptionin EXAMPLE 3, and elsewhere). Following collection of the finishedparticles, the density of the resulting particles is approximately 800particles/mg.

B) Incorporation of Tracer Particles into a Pharmaceutical Formulation

Using a conventional coffee grinder, 300 g of BAYER® Low Dose AspirinPain Reliever, 81 milligram enteric coated tablets are ground to a finepowder (e.g., a dry bulk flow particulate material having particlessmaller than 149 microns in size or passing through a 100 mesh screen).Each tablet contains 81 mg of the active ingredient acetylsalicylicacid, and in addition, the following inactive ingredients: carnauba wax,corn starch, hypromellose, powdered cellulose and triacetin.

In a container suitable for shaking, 3.0 mg (10 ppm) of ferromagnetictracer particles are added to 300 g of the ground aspirin tablet powderand the mixture is shaken for 20 minutes. At the end of that time, theuniform powder is placed into a Desktop Pill Press TDP-1.5 (LondonFashion Arts Co, Oxfordshire, UK). Using 15 KN of pressure, severalhundred aspirin tablets, with a diameter 6 mm and a thickness of 3 mm,are produced within 30 minutes.

C) Isolation and Visualization of Tracer Particles from a SolidPharmaceutical Formulation

Ten (10) grams of the prepared tablets are ground to fine powder (e.g.,a dry bulk flow particulate material having particles smaller than 149microns in size or passing through a 100 mesh screen) using aconventional coffee grinder. The powder is poured into a MicroTracers,Inc., Rotary Detector™ to separate the ferromagnetic tracer particlesfrom the other ingredients (see FIG. 7). The collected tracers(approximately 0.1 mg) are visualized under a stereomicroscope. Theobserved tracer particles retain the microengraved distinguishingmarkings, visible at 200× magnification.

To quantitatively evaluate the rate of tracer recovery, the collectedferromagnetic particles are evenly spread on an 18.5 cm diameter filterpaper. The filter paper is then sprinkled with a developing solutioncomprising potassium ferricyanide (0.1 g), 5.5% aqueous solution ofpotassium hydroxide (2.0 ml), water (20.0 ml) and ethanol (30.0 ml).

The wetted filter paper is transferred to a pre-heated hot plate (100°C.) and heated for 4-5 minutes. Individual tracer particles are countedas bright blue fluorescent spots under a dark camera with UV-light. Thedescribed procedure is performed on at least three filter papers toestimate an average amount of retrieved particles.

Using the estimated average, tracer recovery is also evaluated (e.g.89%) by comparing the actual number of found particles (e.g. 71particles) and the predicted number of particles that wouldhypothetically be contained in 0.1 mg pure tracer (e.g. 80 particles).Alternatively, tracer recovery can be evaluated by comparing the actualnumber of particles recovered from the test sample tablets, to areference standard tablet containing known numbers of tracer particles,where the reference standard tablets are analyzed in parallel with thetest sample tablets using the same methodologies and the sameinstrumentation.

While the foregoing invention has been described in some detail forpurposes of clarity and understanding, it will be clear to one skilledin the art from a reading of this disclosure that various changes inform and detail can be made without departing from the true scope of theinvention. It is to be understood that the invention is not limited toany of the specifically recited methodologies, reagents orinstrumentation that are recited herein, where similar methodologies,reagents or instrumentation can be substituted and used in theconstruction and practice of the invention, and remain within the scopeof the invention. It is also to be understood that the description andterminology used herein is for the purpose of describing particularembodiments of the invention only, and is not intended that theinvention be limited solely to the embodiments described herein.

As used in this specification and the appended claims, singular formssuch as “a”, “an” and “the” include plural referents unless the contentclearly dictates otherwise. For example, reference to “a particle” or“an excipient” also includes a plurality of particles, and combinationsof excipients. All industry and technical terms used herein have thesame meaning as commonly understood by one of ordinary skill in the artor industry to which the invention pertains, unless defined otherwise.

All publications, patents, patent applications, and/or other documentscited in this application are incorporated by reference in theirentirety for all purposes to the same extent as if each individualpublication, patent, patent application, and/or other document wereindividually indicated to be incorporated by reference for all purposes.

What is claimed is:
 1. A population of plasma-etched tracer particles,each particle in the population comprising: a) at least one polymermaterial, said polymer material forming an essentially planar tracerparticle substrate, and b) at least one single plasma etched marking onthe surface of the tracer particle substrate, wherein each dimension ofthe single plasma etched marking is not greater than about 40 microns,where each tracer particle in the population has a predeterminedcircumferential pattern where the circumferential pattern of any onetracer particle is essentially identical to the circumferential patternof at least one other plasma-etched tracer particle in the population;and where each plasma-etched tracer particle in the population is formedby a process that comprises plasma etching the planar substrate in apredetermined circumferential pattern that is the circumferentialpattern of a single tracer particle to a depth that is the fullthickness of the planar substrate, thereby separating individual tracerparticles from each other and forming the population of tracerparticles.
 2. The population of plasma-etched tracer particles of claim1, wherein the largest dimension of the at least one single plasmaetched marking is not greater than about 20 microns.
 3. The populationof plasma-etched tracer particles of claim 1, wherein the largestdimension of the at least one single plasma etched marking is notgreater than about 500 nanometers.
 4. The population of plasma-etchedtracer particles of claim 1, wherein the predetermined circumferentialpattern is characterized by a width dimension and a length dimension. 5.The population of plasma-etched tracer particles of claim 1, whereineach plasma-etched tracer particle does not exceed about 400 microns inany dimension.
 6. The population of plasma-etched tracer particles ofclaim 1, wherein each plasma-etched tracer particle does not exceedabout 100 microns in any dimension.
 7. The population of plasma-etchedtracer particles of claim 1, wherein each plasma-etched tracer particlefurther comprises one or more materials selected from colored material,colorimetric agent, chromogenic material, chromophore, thermochromicmaterial, fluorescent material, fluorogenic material, fluorometricagent, fluorophore, a dye and a pigment.
 8. A marked product comprisinga population of plasma-etched tracer particles of claim
 1. 9. The markedproduct of claim 8, wherein the marked product is a flowable dry bulkmaterial.
 10. The marked product of claim 8, wherein the marked productis a liquid bulk material.
 11. The marked product of claim 8, whereinthe marked product is an explosive material.
 12. A marked pharmaceuticalproduct comprising (i) at least one active ingredient that is dispersedin an excipient, and (ii) the population of plasma-etched tracerparticles of claim 1, wherein: (A) the plurality of plasma-etched tracerparticles are dispersed in the excipient, or (B) the pharmaceuticalproduct comprises a coating or capsule, where the plurality ofplasma-etched tracer particles are associated with the coating orcapsule.
 13. The marked pharmaceutical product of claim 12, wherein theexcipient is selected from solid formulation excipients and liquidformulation excipients.
 14. The population of plasma-etched tracerparticles of claim 1, wherein each plasma-etched tracer particle in thepopulation consists essentially of materials generally regarded as safefor human consumption.
 15. A population of plasma-etched tracerparticles, each particle in the population comprising: a) at least onepolymer material, said polymer material forming an essentially planartracer particle substrate, and b) at least one single plasma etchedmarking on the surface of the tracer particle substrate, where eachtracer particle in the population has a predetermined circumferentialpattern where the circumferential pattern of any one tracer particle isessentially identical to the circumferential pattern of at least oneother plasma-etched tracer particle in the population, and where eachplasma-etched tracer particle in the population is formed by a processthat comprises plasma etching the planar substrate in a predeterminedcircumferential pattern that is the circumferential pattern of a singletracer particle to a depth that is the full thickness of the planarsubstrate, thereby separating individual tracer particles from eachother and forming the population of tracer particles, where eachplasma-etched tracer particle in the population does not exceed about400 microns in any dimension.
 16. The population of plasma-etched tracerparticles of claim 14, wherein each plasma-etched tracer particle doesnot exceed about 100 microns in any dimension.
 17. The population ofplasma-etched tracer particles of claim 14, wherein each plasma-etchedtracer particle does not exceed about 50 microns in any dimension. 18.The population of plasma-etched tracer particles of claim 14, whereinthe largest dimension of the at least one single plasma etched markingis not more than 40 microns.
 19. The population of plasma-etched tracerparticles of claim 14, wherein the largest dimension of the at least onesingle plasma etched marking is not more than 20 microns.
 20. Thepopulation of plasma-etched tracer particles of claim 14, wherein thelargest dimension of the at least one single plasma etched marking isnot more than 5 microns.
 21. The population of plasma-etched tracerparticles of claim 14, wherein the largest dimension of the at least onesingle plasma etched marking is not more than 500 nanometers.